KR20070010144A - Novel gamma secretase inhibitors - Google Patents

Abstract

Chemical formula should be inserted here as it appears on the abstract in paper form. are useful in treating various neurodegenerative diseases, wherein, for example: R1 includes unsubstituted or substituted aryl or heteroaryl groups; R2 includes -C(O)-Y, alkylene-C(O)-Y, alkylene- cycloalkylene-C(O)-Y, cycloalkylene-alkylene-C(O)-Y, alkylene cycloalkylene-alkylene-C(O)-Y, cycloalkylene-C(O)-Y, -S(O)-Y, alkylene- S(O)-Y, alkylene-cycloalkylene-S(O)-Y, cycloalkylene-alkylene-S(O)-Y, alkylene cycloalkylene-alkylene-S(O)-Y, cycloalkylene-S(O)-Y, -S(O2)-Y, alkylene-S(O2)-Y, alkylene cycloalkylene S(O2)-Y, cycloalkylene alkylene S(O2)-Y, alkylene cycloalkylene-alkylene-S(O2)-Y, and cycloalkylene-S(O2)- Y, wherein Y is as defined herein, and each of said alkylene or cycloalkylene may be unsubstituted or substituted as provided herein; each R3 is independently includes H, alkyl, O alkyl, OH, N(R9)2, acyl, and aroyl; or the moiety (R3)2, together with the ring carbon atom to which it is shown attached in formula I, defines a carbonyl group, -C(O)-; each R3A and R3B independently includes H, or alkyl; R11 includes aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, or alkoxyalkyl. One or more of the compounds of formula I, or pharmaceutically acceptable salts, solvates, and/or esters, or compositions comprised thereof, may be used to treat, e.g., Alzheimer's Disease. ® KIPO & WIPO 2007

Description

Novel gamma secretase inhibitors

WO 00/50391, published August 13, 2000, describes compounds having sulfonamide residues that are useful for treating and preventing Alzheimer's disease and other diseases associated with amyloid protein deposition. .

In view of the current interest in the treatment or prevention of neurodegenerative diseases (eg Alzheimer's disease), compounds for use in such treatment or prevention are of considerable benefit in the art. The present invention contributes to this.

Summary of the Invention

The present invention provides compounds of formula (I), or pharmaceutically acceptable salts, solvates and / or esters thereof, which are inhibitors (eg antagonists) of gamma secretase:

Where

R ¹ is selected from the group consisting of unsubstituted aryl, aryl substituted by one or more R ⁵ groups, unsubstituted heteroaryl, and heteroaryl substituted by one or more R ⁵ groups;

R ² is —C (O) —Y, —alkylene-C (O) —Y, —alkylene-cycloalkylene-C (O) —Y, —cycloalkylene-alkylene-C (O) — Y, -alkylene-cycloalkylene-alkylene-C (O) -Y, -cycloalkylene-C (O) -Y, -S (O) -Y, -alkylene-S (O) -Y , -Alkylene-cycloalkylene-S (O) -Y, -cycloalkylene-alkylene-S (O) -Y, -alkylene-cycloalkylene-alkylene-S (O) -Y,- Cycloalkylene-S (O) -Y, -S (O ₂ ) -Y, -alkylene-S (O ₂ ) -Y, -alkylene-cycloalkylene-S (0 ₂ ) -Y, -cyclo an alkylene-alkylene -S (O ₂₎ -Y, - alkylene-cycloalkylene-alkylene -S (O ₂₎ -Y, and - cycloalkylene -S (O ₂₎ from the group consisting of -Y Selected; Wherein each of said alkylene or cycloalkylene is unsubstituted or optionally substituted by one or more hydroxy groups, provided no hydroxy group is bonded to a carbon atom, wherein the carbon atom is also bonded to a sulfur atom ;

Each R ³ is independently selected from the group consisting of H, alkyl, —O-alkyl, —OH, —N (R ⁹ ) ₂ , acyl and aroyl; or

Residue (R ³ ) ₂ , together with the ring carbon atom shown as bound in formula (I), defines a carbonyl group, -C (O)-, provided that at most one carbonyl group when m is an integer greater than 1 Is present in the ring represented by formula (I);

Each R ^3A And R ^3B is independently selected from the group consisting of H and alkyl;

R ⁵ is halo, -CF ₃ . -OH, alkoxy, -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl, -OC (O) -alkyl, -C (O) O-aryl, -OC (O) -aryl, -C (O) NR ⁶ R ⁷ , -alkylene-NR ⁶ R ⁷ , -N (R ⁶ ) C (O) -alkyl, -N (R ⁶ ) C (O) -aryl, -N (R ⁶ ) C (O) -heteroaryl, and -N (R ⁶ ) C (O) NR ⁶ R ⁷ are independently selected from the group consisting of;

Y is —NR ⁶ R ⁷ , —N (R ¹² ) (CH ₂ ) _b NR ⁶ R ⁷ , wherein b is an integer from 2 to 6, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, Arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, aryl alkyl heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted arylcycloalkyl, substituted Heteroarylalkyl, substituted heteroarylcycloalkyl, substituted arylheterocycloalkyl, and substituted heterocycloalkyl alkyl; Wherein said substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted arylcycloalkyl, substituted heteroarylalkyl, substituted heteroarylcycloalkyl, substituted arylheterocycloalkyl, or substituted heterocyclo of the Y group The aryl or heteroaryl moiety in the alkyl alkyl group is halo, -CF ₃ , -OH, alkoxy, -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl, -OC (O) -alkyl,- C (O) O-aryl, -OC (O) -aryl, -C (O) NR ⁶ R ⁷ , -alkylene-NR ⁶ R ⁷ , -N (R ⁶ ) C (O) -alkyl, -N One independently selected from the group consisting of (R ⁶ ) C (O) -aryl, -N (R ⁶ ) C (O) -heteroaryl, -N (R ⁶ ) C (O) NR ⁶ R ⁷ , and alkyl Substituted with one or more substituents; or

Y is

Is selected from the group consisting of;

R ⁶ and R ⁷ are H, alkyl, alkyl substituted with 1 to 4 hydroxy groups, cycloalkyl, arylalkyl, heteroarylalkyl,

, 및 헤테로사이클로알킬로 이루어진 그룹으로부터 독립적으로 선택되고, 단 R⁶ 및/또는 R⁷이 1 내지 4개의 하이드록시 그룹으 로 치환된 알킬인 경우, 하이드록시 그룹들 중의 어느 것도 탄소[여기서, 당해 탄소에는 또한 질소가 결합된다]에 결합되지 않으며;

And independently selected from the group consisting of heterocycloalkyl, provided that when R ⁶ and / or R ⁷ is alkyl substituted with 1 to 4 hydroxy groups, none of the hydroxy groups are carbon [wherein Carbon is also bonded to nitrogen;

R ⁸ is independently selected from the group consisting of H, —OH, alkyl, —O-alkyl, alkyl substituted with 1 to 4 hydroxy groups, and —C (O) O-alkyl; Or when r is at least 1 and at least two R ⁸ groups are selected from the group consisting of alkyl, -O-alkyl, alkyl substituted with 1 to 4 hydroxy groups, and -C (O) O-alkyl, R ⁸ groups together with the ring carbon atom or atoms to which they are attached define a ring;

Each R ⁹ is H, alkyl, alkyl substituted by 1 to 4 hydroxy groups, cycloalkyl, cycloalkyl substituted by 1 to 4 hydroxy groups, arylalkyl, heteroarylalkyl, -C (O) O -alkyl, -alkyl-alkylene -O- alkylene -OH, at least one R ⁵ group, an aryl substituted aryl, heteroaryl substituted with one or more R ⁵ groups, unsubstituted heteroaryl, unsubstituted, - alkylene- Independently selected from the group consisting of C (O) O-alkyl,-(SO ₂ ) -alkyl,-(SO ₂ ) -aryl, and hydroxyalkyl-O-alkyl; Provided that when R ⁹ is alkyl substituted with 1 to 4 hydroxy groups, none of the hydroxy groups are bonded to carbon, wherein the carbon is also bonded to nitrogen;

Each R ¹⁰ is independently selected from the group consisting of H and alkyl;

R ¹¹ is aryl, substituted aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, alkoxyalkyl, substituted heteroaryl, substituted arylalkyl , Substituted arylcycloalkyl, substituted heteroarylalkyl, and substituted arylheterocycloalkyl; Wherein the aryl or heteroaryl moiety in the substituted heteroaryl, substituted arylalkyl, substituted arylcycloalkyl, substituted heteroarylalkyl, and substituted arylheterocycloalkyl of the R ¹¹ group is halo, -CF ₃ ,- OH, alkoxy, -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl, -OC (O) -alkyl, -C (O) O-aryl, -OC (O) -aryl,- C (O) NR ⁶ R ⁷ , -alkylene-NR ⁶ R ⁷ , -N (R ⁶ ) C (O) -alkyl, -N (R ⁶ ) C (O) -aryl, -N (R ⁶ ) Substituted with one or more substituents independently selected from the group consisting of C (O) -heteroaryl, and -N (R ⁶ ) C (O) NR ⁶ R ⁷ ;

R ¹² is H, alkyl, aryl, and halo, -CF ₃ , -OH, alkoxy, -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl, -OC (O) -alkyl,- C (O) O-aryl, -OC (O) -aryl, -C (O) NR ⁶ R ⁷ , -alkylene-NR ⁶ R ⁷ , -N (R ⁶ ) C (O) -alkyl, -N One or more substituents independently selected from the group consisting of (R ⁶ ) C (O) -aryl, -N (R ⁶ ) C (O) -heteroaryl, and -N (R ⁶ ) C (O) NR ⁶ R ⁷ It is selected from the group consisting of aryl substituted with;

m is an integer from 0 to 3, and when m is greater than 1, the m residues may be the same or different from each other;

n is an integer from 0 to 3 and when n is greater than 1, the n residues may be the same or different from each other;

o is an integer from 0 to 3, and when o is greater than 1, o residues may be the same or different from each other;

Provided that m + n + o is 1, 2, 3 or 4;

p is an integer from 0 to 4, and if p is greater than 1, the p residues may be the same or different from each other;

r is an integer from 0 to 4 and when r is greater than 1, the r residues may be the same or different from each other;

s is an integer from 0 to 3, and when s is greater than 1, the s residues may be the same or different from each other;

Z is heterocycloalkyl, substituted heterocycloalkyl, -NH ₂ , -NH (alkyl), -N (alkyl) ₂ , wherein each alkyl is the same or different], -NH (cycloalkyl), -NH (Substituted cycloalkyl), -N (alkyl) (cycloalkyl), -N (alkyl) (substituted cycloalkyl), -NH (aralkyl), -NH (substituted aralkyl), -N (alkyl) (Aralkyl), -NH (heterocycloalkyl), -NH (substituted heterocycloalkyl), -N (alkyl) (heterocycloalkyl), -N (alkyl) (substituted heterocycloalkyl), -NH ( Heteroaralkyl), -NH (substituted heteroaralkyl), -NH-alkylene- (cycloalkyl), -NH-alkylene- (substituted cycloalkyl), -N (alkyl) -alkylene- (cyclo Alkyl), -N (alkyl) -alkylene- (substituted cycloalkyl), -NH-alkylene- (heterocycloalkyl), -NH-alkylene- (substituted heterocycloalkyl), -N (alkyl) -Alkylene- (heterocycloalkyl), -N (alkyl) -alkylene- (substituted heterocyclo Kiel), benzo fused heterocycloalkyl, substituted benzo-fused heterocycloalkyl, H, and -N (hydroxyalkyl) _2; wherein each alkyl is the same or different; is selected from the group consisting of; Wherein said substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl moiety of the Z group is alkyl, -OH, alkoxy, -OC (O) -alkyl, -OC (O) -aryl, -NH ₂ , -NH (alkyl)-, -N (alkyl) ₂ , wherein each alkyl is the same or different, -NHC (O) -alkyl, -N (alkyl) C (O) -alkyl, -NHC (O) aryl-, -N (alkyl) C (O) -aryl, -C (O) -alkyl, -C (O) -aryl, -C (O) NH ₂ , -C (O) NH (Alkyl), -C (O) N (alkyl) ₂ , wherein each alkyl is the same or different, -C (O) O-alkyl, -alkylene-C (O) O-alkyl, piperidi Substituted by one or more substituents independently selected from the group consisting of nil, pyrrolidinyl, aryl, heteroaryl, and -O-CH ₂ CH ₂ -O-, wherein two oxygen atoms are bonded to the same carbon atom Provided that the aryl and heteroaryl moieties of the Z group are not substituted by the -O-CH ₂ CH ₂ -O- group.

The present invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula (I) and at least one pharmaceutically acceptable carrier.

The present invention also provides a method of inhibiting gamma-secretase, including administering an effective amount (ie, a therapeutically effective amount) of one or more compounds of Formula (I) above to a patient in need of inhibition.

The invention also provides a method of treating one or more neurodegenerative diseases, including administering an effective amount (ie, a therapeutically effective amount) of one or more compounds of Formula (I) to a patient in need thereof.

The invention also includes administering an effective amount (ie, a therapeutically effective amount) of one or more of the compounds of Formula (I) to a patient in need thereof, within, on, or around a neurological tissue (eg, the brain). A method of inhibiting the deposition of amyloid protein (eg amyloid beta protein) is provided.

The present invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount (ie, a therapeutically effective amount) of one or more compounds of formula (I) to a patient in need thereof.

In one embodiment, the present invention provides a compound of formula (I), as described above.

In another embodiment of compounds of Formula (I), R ² is-(C ₀ -C ₁₂ ) alkylene-C (0) -Y,-(C ₀ -C ₆ ) alkylene- (C ₃ -C ₆ ) cyclo Alkylene- (C ₀ -C ₆ ) alkylene-C (0) -Y,-(C ₀ -C ₁₂ ) alkylene-S (O) -Y,-(C ₀ -C ₆ ) alkylene- ( C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (0) -Y,-(C ₀ -C ₁₂ ) alkylene-S (0 ₂ ) -Y, or-(C _0- C ₆ ) alkylene- (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (0) ₂ -Y.

In another embodiment of compounds of Formula (I), R ² is-(C ₃ -C ₆ ) cycloalkylene-C (0) -Y.

In another embodiment of compounds of Formula (I), R ² is -cyclopropylene-C (O) -Y.

In another embodiment of compounds of Formula (I), R ² is-(C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-C (0) -Y.

In another embodiment of compounds of Formula (I), R ² is — (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene (OH) -C (0) -Y.

In another embodiment of compounds of Formula (I), R ² is -cyclopropylene-CH ₂ -C (0) -Y.

In another embodiment of compounds of Formula (I), R ² is -cyclopropylene-CH (OH) -C (0) -Y.

In another embodiment of compounds of Formula (I), R ² is — (C ₃ -C ₆ ) cycloalkylene-S (O ₂ ) —Y.

In another embodiment of compounds of Formula (I), R ² is -cyclopropylene-S (O ₂ ) -Y.

In another embodiment of compounds of Formula (I), R ² is — (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (O ₂ ) —Y.

In another embodiment of compounds of Formula (I), R ² is -cyclopropylene-CH ₂ -S (O ₂ ) -Y.

In another embodiment of the compound of formula (I), Y is

이다.

to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

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to be.

In another embodiment of the compound of formula (I), Y is

이다.

to be.

In another embodiment of the compound of formula (I), Y is

이다.

to be.

In another embodiment of the compounds of formula (I), Y is —N (CH ₂ CH ₂ OH) ₂ .

In another embodiment of compounds of Formula (I), R ² is-(C ₀ -C ₁₂ ) alkylene-C (O) -Y,-(C ₀ -C ₆ ) alkylene- (C ₃ -C ₆ ) cyclo Alkylene- (C ₀ -C ₆ ) alkylene-C (0) -Y,-(C ₀ -C ₁₂ ) alkylene-S (0) -Y,-(C ₀ -C ₆ ) alkylene- ( C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (0) -Y,-(C ₀ -C ₁₂ ) alkylene-S (O ₂ ) -Y, or-(C _0- C ₆ ) alkylene- (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (0 ₂ ) -Y, Y is

It is selected from the group consisting of.

In another embodiment of the compound of formula (I), R ² is

이다.

to be.

In another embodiment of the compound of formula (I), R ² is

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to be.

In another embodiment of the compound of formula (I), R ² is

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to be.

In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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In another embodiment of the compound of formula (I), R ² is

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to be.

In another embodiment of the compound of formula (I), R ² is

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to be.

In another embodiment of the compound of formula (I), R ² is

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to be.

In another embodiment of compounds of Formula (I), R ² is-(C ₀ -C ₁₂ ) alkylene-C (0) -Y,-(C ₀ -C ₆ ) alkylene- (C ₃ -C ₆ ) cyclo Alkylene- (C ₀ -C ₆ ) alkylene-C (0) -Y,-(C ₀ -C ₁₂ ) alkylene-S (0) -Y,-(C ₀ -C ₆ ) alkylene- ( C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (0) -Y,-(C ₀ -C ₁₂ ) alkylene-S (0 ₂ ) -Y, or-(C _0- C ₆ ) alkylene- (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (0 ₂ ) -Y;

Y is:

이고;

ego;

(R ³⁾ each R ³ ₂ is _{H, -OH, - (C 1} -C 6) alkyl, -O- (C ₁ -C _{6) ^{alkyl, -N (R 9) 2,}} - (C 1 -C ₆ ) acyl and-(C ₇ -C ₁₃ ) aroyl;

Each of R ^3A and R ^3B is independently selected from the group consisting of H and — (C ₁ -C ₆ ) alkyl;

R ⁵ is independently selected from the group consisting of halo, —OH, —CF ₃ , and —O— (C ₁ -C ₆ ) alkyl;

R ¹¹ is-(C ₆ -C ₁₂ ) aryl, substituted-(C ₃ -C ₁₂ ) aryl,-(C ₆ -C ₁₂ ) heteroaryl, and substituted-(C ₆ -C ₁₂ ) heteroaryl Selected from the group consisting of: wherein substituted-(C ₆ -C ₁₂ ) aryl and substituted-(C ₆ -C ₁₂ ) heteroaryl are at least one halo, -CF ₃ , -OH, or -O- (C ₁ -C ₆ ) alkyl group;

m is 0 or 1;

n is O or 1;

o is O or 1;

In yet another embodiment of the compound of Formula (I), R ² is-(C ₀ -C ₁₂ ) alkylene-C (O) -Y and-(C ₀ -C ₆ ) alkylene- (C ₃ -C ₆ ) Cycloalkylene- (C ₀ -C ₆ ) alkylene-C (O) -Y;

Y is

로 이루어진 그룹으로부터 선택되고;

Is selected from the group consisting of;

(R ³⁾ each R ³ ₂ is _{H, -OH, - (C 1} -C 6) alkyl, -O- (C ₁ -C _{6) ^{alkyl, -N (R 9) 2,}} - (C 1 -C ₆ ) acyl and-(C ₇ -C ₁₃ ) aroyl;

(R ³ ) ₂ together with the ring carbon shown as attached in formula (I), define a carbonyl group, provided that when m is an integer of at least 1, at most one carbonyl group is present in the ring represented by formula (I);

Each of R ^3A and R ^3B is independently selected from the group consisting of H and (C ₁ -C ₆ ) alkyl;

R ⁵ is independently selected from the group consisting of halo, —OH, —CF ₃ , and —O— (C ₁ -C ₆ ) alkyl;

R ⁸ is H, —OH, — (C ₁ -C ₆ ) alkyl, —O— (C ₁ -C ₆ ) alkyl, — (C ₁ -C ₆ ) alkyl substituted with a hydroxy group, and C (O If the (C ₁ -C ₆₎ alkyl _{-) O- (C 1 -C 6} ) independently selected from the group consisting of alkyl and, with the proviso that R ⁸ is -OH, or a hydroxyl group substituted by hydroxy;

R ⁹ is independently selected from the group consisting of H. alkyl and-(C ₁ -C ₆ ) alkyl substituted with a hydroxy group, provided that R ⁹ is substituted with a hydroxy group-(C ₁ -C ₆ ) In the case of alkyl, no hydroxy group is attached to a carbon atom, wherein the carbon atom is bonded to a nitrogen atom;

R ¹¹ is selected from the group consisting of (C ₆ -C ₁₂ ) aryl, substituted (C ₆ -C ₁₂ ) aryl, (C ₆ -C ₁₂ ) heteroaryl, and substituted (C ₆ -C ₁₂ ) heteroaryl Wherein the substituted (C ₆ -C ₁₂ ) aryl and substituted (C ₆ -C ₁₂ ) heteroaryl are one or more halo, —CF ₃ , —OH, or —O— (C ₁ -C ₃ ) alkyl group Substituted with;

Z is selected from the group consisting of heterocycloalkyl:

m is 0 or 1;

n is O or 1;

o is O or 1;

In yet another embodiment of compounds of Formula (I), R ¹ is unsubstituted aryl or aryl substituted with one or more R ⁵ groups.

In still another embodiment of the compound of formula (I), R ¹ is phenyl.

In yet another embodiment of the compound of Formula (I), R ¹ is phenyl substituted with one or more R ⁵ groups.

In yet another embodiment of compounds of Formula (I), R ¹ is phenyl substituted with one or more halo atoms.

In yet another embodiment of the compound of Formula (I), R ¹ is phenyl substituted with one halo atom.

In yet another embodiment of compounds of Formula (I), R ¹ is phenyl substituted with chloro (eg p-chlorophenyl).

In yet another embodiment of the compound of Formula (I), R ¹ is unsubstituted heteroaryl (eg, pyridyl, pyrimidyl, pyridazyl, pyrazyl) or heteroaryl substituted with one or more R ⁵ groups.

In still another embodiment of the compounds of formula (I), R ² is -C (O) Y, - ( C 1 -C 6) alkylene -C (O) -Y, - ( C 3 -C 6) cycloalkylene -C (O) -Y,-(C ₃ -C ₆ ) cycloalkylene- (C ₁ -C ₆ ) alkylene-C (O) -Y, or-(C ₁ -C ₆ ) alkylene- ( C ₃ -C ₆ ) cycloalkylene- (C ₃ -C ₆ ) alkylene-C (O) -Y.

In still another embodiment of the compound of Formula (I), R ² is-(C ₃ -C ₆ ) cycloalkylene-C (O) -Y or-(C ₃ -C ₆ ) cycloalkylene- (C ₁ -C ₆ ) alkylene-C (0) -Y.

In yet another embodiment of compounds of Formula (I), R ² is cyclopropylene- (C ₁ -C ₆ ) alkylene-C (O) -Y or cyclopropylene-C (O) —Y.

In yet another embodiment of the compound of Formula (I), R ² is cyclopropylene-CH ₂ -C (O) -Y or cyclopropylene-C (O) -Y.

In still another embodiment of the compounds of formula (I), R ² is -S (O) Y, - ( C 1 -C 6) alkylene -S (O) -Y, - ( C 3 -C 6) cycloalkylene -S (O) -Y,-(C ₃ -C ₆ ) cycloalkylene- (C ₁ -C ₃ ) alkylene-S (O) -Y, or-(C ₁ -C ₆ ) alkylene- ( C ₃ -C ₆ ) cycloalkylene- (C ₁ -C ₆ ) alkylene-S (O) -Y.

In yet another embodiment of the compound of Formula (I), R ² is-(C ₃ -C ₆ ) cycloalkylene-S (O) -Y or-(C ₃ -C ₆ ) cycloalkylene- (C ₁ -C ₆ ) alkylene-S (O) -Y.

In still another embodiment of the compounds of formula (I), R ² is - a cycloalkyl propylene -S (O) -Y-cycloalkyl propylene - (C ₁ -C ₆₎ alkylene -S (O) -Y or.

In yet another embodiment of the compound of Formula (I), R ² is -cyclopropylene-CH ₂ -S (O) -Y or -cyclopropylene-S (O) -Y.

In yet another embodiment of the compound of Formula (I), R ² is -S (O ₂ ) Y,-(C ₁ -C ₆ ) alkylene-S (O ₂ ) -Y,-(C ₃ -C ₆ ) cyclo Alkylene-S (O ₂ ) -Y,-(C ₃ -C ₆ ) cycloalkylene- (C ₁ -C ₆ ) alkylene-S (O ₂ ) -Y, or-(C ₁ -C ₆ ) Alkylene- (C ₃ -C ₆ ) cycloalkylene- (C ₁ -C ₆ ) alkylene-S (O ₂ ) —Y.

In yet another embodiment of the compound of Formula (I), R ² is-(C ₃ -C ₆ ) cycloalkylene-S (O 2) -Y or-(C ₃ -C ₆ ) cycloalkylene- (C ₁ -C ₆ ) alkylene-S (O ₂ ) -Y.

In still another embodiment of the compounds of formula (I), R ² is - a cycloalkyl propylene -S (O ₂₎ -Y-cycloalkyl propylene - (C ₁ -C ₆₎ alkylene -S (O ₂₎ -Y or.

In yet another embodiment of the compound of Formula (I), R ² is cyclopropylene-CH ₂ —S (O ₂ ) —Y or —cyclopropylene-S (O ₂ ) —Y.

In still another embodiment of the compounds of formula (I), (R ³⁾ each of R ³ ₂ are independently _{H, -OH, -NH 2, -NH} (SO 2) - alkyl, -NH (SO ₂₎ - aryl ,-(C ₂ -C ₆ ) acyl (eg acetyl), or (C ₇ -C ₁₃ ) aroyl (eg benzoyl).

In still another embodiment of the compounds of formula (I), (R ³⁾ each of R ³ ₂ is H.

In yet another embodiment of the compound of Formula (I), (R ³ ) ₂ defines a carbonyl group with the ring carbon shown to be bonded to formula (I), provided that when m is an integer of 1 or more, one or more carbonyl groups It is present in the ring shown in formula (I).

In yet another embodiment of the compound of formula (I), (R ³ ) ₂ defines a carbonyl group with the ring carbon shown as bonded in formula (I), and m is 1.

In yet another embodiment of the compound of Formula (I), each R ^3A and R ^3B is independently H or (C ₁ -C ₆ ) alkyl (eg methyl, ethyl, n-propyl, i-propyl, n-butyl, Secondary-butyl, t-butyl, n-pentyl, neo-pentyl, or hexyl).

In yet another embodiment of compounds of Formula (I), each R ^3A and R ^3B is H.

In yet another embodiment of the compound of Formula (I), each R ⁵ is independently halo (eg Cl), -CF ₃ , -OH, alkoxy (eg methoxy), -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl (eg -C (O) O-CH ₃ or -C (O) O-CH ₂ CH ₃ ), -OC (O) -alkyl (eg -OC (O) -CH ₃ ), -C (O) O-aryl (eg -C (O) O-phenyl), -OC (O) -aryl (eg -OC (O) -phenyl), -C (O) NR ⁶ R ⁷ (eg -C (O) N (CH ₃ ) ₂ ), -alkylene-NR ⁶ R ⁷ (eg -CH ₂ -N (CH ₃ ) ₂ or -CH ₂ CH ₂ -N ( CH ₃ ) ₂ ), -N (R ⁶ ) C (O) -alkyl (e.g., -N (CH ₃ ) C (O) -CH ₃ or -NHC (O) -CH ₃ ), -N (R ⁶ ) C (O) -aryl (eg -N (CH ₃ ) C (O) -phenyl or -NHC (O) -phenyl), -N (R ⁶ ) C (O) -heteroaryl (eg -N (CH ₃ ) C (O) -pyridyl or -NHC (O) -pyridyl), or -N (R ⁶ ) C (O) NR ⁶ R ⁷ (eg -N (CH ₃ ) C (O) N (CH ₃ ) ₂ or -NHC (O) N (CH ₃ ) ₂ ).

In yet another embodiment of the compound of Formula (I), Y is selected from the group consisting of:

.

.

In yet another embodiment of compounds of Formula (I), Y is

이고;

ego;

r is 2;

One R ⁸ is — (C ₁ -C ₆ ) alkyl, the second R ⁸ is —O— (C ₁ -C ₆ ) alkyl and the two R ⁸ groups together with the ring carbon atoms to which they are attached, To form a polycyclic ring structure.

In yet another embodiment of compounds of Formula (I), Y is

이고;

ego;

r is 2;

One R ⁸ is — (C ₁ -C ₆ ) alkyl, the second R ⁸ is —O— (C ₁ -C ₆ ) alkyl, and two R ⁸ groups are bonded to the same ring carbon atom, to which they are attached Together with ring carbon atoms, two R ⁸ groups define a spirocyclic ring.

In yet another embodiment of compounds of Formula (I), Y is

이다.

to be.

In yet another embodiment of the compound of Formula (I), R ⁶ and R ⁷ are H, methyl, ethyl, hydroxyethyl,-(C ₃ -C ₈ ) cycloalkyl, -aryl (C ₁ -C ₆ ) alkyl, 4 Pyridylmethyl,

로 이루어진 그룹으로부터 독립적으로 선택된다.

It is independently selected from the group consisting of.

In yet another embodiment of compounds of Formula (I), R ⁸ is H, —OH, methyl, methoxy, ethoxy, —C (O) O—CH ₃ , —C (O) O—CH ₂ CH _3, or -(C ₁ -C ₆ ) alkyl substituted with 1 to 4 —OH groups.

In yet another embodiment of the compound of formula (I), R ⁸ is H, methyl, methoxy, hydroxyethyl or hydroxymethyl.

In yet another embodiment of the compound of Formula (I), r is 2 and R ⁸ is —OH and —C (O) O— (C ₁ -C ₆ ) alkyl.

In yet another embodiment of the compound of Formula (I), r is 2 and R ⁸ is -OH and hydroxymethyl.

In yet another embodiment of the compound of Formula (I), R ⁸ is hydroxymethyl and Z is N-morpholinyl.

In yet another embodiment of the compound of Formula (I), R ⁸ is H and R ⁹ is hydroxyethyl.

In yet another embodiment of compounds of Formula (I), R ⁸ is H and R ⁹ is methyl.

In yet another embodiment of the compound of Formula (I), at least one R ⁸ is methyl and R ⁹ is hydroxyethyl.

In yet another embodiment of compounds of Formula (I), at least one R ⁸ is methyl and R ⁹ is methyl.

In yet another embodiment of the compound of Formula (I), at least one R ⁸ is methyl and R ⁹ is H.

In still another embodiment of compounds of formula I, R ⁹ is H, - (C ₁ -C ₆₎ alkyl (e.g. methyl), one to four -OH group with a substituted - (C ₁ -C ₆₎ alkyl (E.g.-(CH ₂ ) ₂ OH),-(C ₁ -C ₆ ) alkyl-O- (C ₁ -C ₆ ) alkyl-OH (e.g. 2- (2-hydroxyethoxy) ethyl), (C ₃ -C ₈ ) cycloalkyl, or heteroaryl, provided that R ⁹ is not hydroxymethyl.

In yet another embodiment of the compound of Formula (I), R ⁹ is H, methyl, cyclohexyl, 2-pyridyl, 2-hydroxyethyl or 2- (2-hydroxyethoxy) ethyl.

In yet another embodiment of the compound of Formula (I), R ¹⁰ is H or-(C ₁ -C ₆ ) alkyl.

In yet another embodiment of compounds of Formula (I), R ¹⁰ is H or methyl.

In yet another embodiment of compounds of Formula (I), R ¹⁰ is H.

In yet another embodiment of the compound of Formula (I), R ¹¹ is-(C ₁ -C ₆ ) alkyl (eg methyl or ethyl), (C ₃ -C ₈ ) -cycloalkyl (eg cyclopropyl), aryl ( Examples: phenyl), aryl (C ₁ -C ₆ ) alkyl (eg benzyl or-(CH ₂ ) ₂ phenyl) and-(C ₁ -C ₆ ) alkoxyalkyl (eg -CH ₂ OCH ₃ ) Is selected from.

In yet another embodiment, the compound of formula (I) is represented by the following structure:

.

.

In yet another embodiment, the compound of formula (I) is represented by the following structure:

.

.

In yet another embodiment, the compound of formula (I) is selected from the group consisting of the following compounds, or pharmaceutically acceptable salts, solvates and / or esters thereof:

In yet another embodiment, the compound of formula (I) is selected from the group consisting of the following compounds, or pharmaceutically acceptable salts, solvates and / or esters thereof:

.

.

Each reference to a residue, eg, “m residue”, preceded by an index means a residue quantified by this index. Thus, for example, the term “m residue” means a residue whose amount is represented by the index “m”.

As noted above and throughout this specification, unless otherwise indicated, the following terms should be understood to have the following meanings:

"AcOH" means acetic acid.

"BOP" means benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium hexaphosphate.

"cat." means catalytic amount.

"Cp" means cyclopentadienyl.

"DCE" means dichloroethane.

"DCM" means dichloromethane.

"DIBAL" means diisobutylaluminum hydride.

"EDCl" means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.

"Et" means ethyl.

"H ₃ O ⁺ " means aqueous acid.

"ΗATU" means 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate.

"HOBT" means 1-hydroxybenzotriazole hydrate.

"LAH" means lithium aluminum hydride.

"LDA" means lithium diisopropylamide.

"MCPBA" means m-chloroperoxybenzoic acid.

"Me" means methyl.

"MsCl" means methanesulfonyl chloride.

"NMM" means N-methylmorpholine.

"t-Bu" means tert-butyl.

"Ph" means phenyl.

"TBSCl" means tert-butyldimethylsilyl chloride.

"TBSOTf" means tert-butyldimethylsilyltrifluoromethanesulfonate.

"TBS" means t-butyldimethylsilyl.

"TBAF" means tetrabutylammonium fluoride.

을 의미한다."Tebbe Reagent"

Means.

"TEMPO" means 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical.

"Tf" means trifluoromethylsulfonyl.

"THF" means tetrahydrofuran.

"TLC" means thin layer chromatography.

"Ts" means toluene sulfonyl (also referred to as "tosyl").

"Patient" includes both humans and animals.

"Mammal" means humans and other mammals.

The term "substituted" means that one or more hydrogens on the specified atom are replaced with ones selected from the group indicated, provided that the valences of the specified atoms under the present conditions do not exceed, and that substitution results in stable compounds. . Combinations of substituents and / or variables can only be tolerated if such combinations produce stable compounds. "Stable compound" or "stable structure" means a compound that is sufficiently stable to withstand a useful degree of purity from the reaction mixture and to form into an effective therapeutic agent.

The term "optionally substituted" means any substitution by a specified group, radical or moiety.

The term "isolated" or "isolated form" for a particular compound refers to the physical state of that compound after separation from the synthetic process or its natural raw materials or mixtures. The term "purified" or "purified form" for a particular compound is described herein or to those skilled in the art in sufficient purity that may be characterized by standard analytical techniques described herein or known to those skilled in the art. Physical state of the compound after it has been obtained from the prepared purification method or methods.

"Alkyl" means an aliphatic hydrocarbon group having from about 1 to about 20 carbon atoms in the chain and may be straight or branched. Preferred alkyl groups have from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups have from about 1 to about 6 carbon atoms in the chain. By side chain is meant one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the straight carbon chain. "Lower alkyl" refers to a group having from about 1 to about 6 carbon atoms in the chain, which may be straight or branched. The term "substituted alkyl" may be substituted with one or more substituents in which the alkyl groups may be the same or different. Wherein each substituent is halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl) ₂ , Independently selected from the group consisting of carboxy, -C (O) O-alkyl and -S (alkyl). Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl and cyclopropylmethyl Independently selected from the group consisting of.

"Alkenyl" means an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, which may be straight or branched, and has from about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain; More preferably, there are about 2 to about 6 carbon atoms in the chain. By side chain is meant one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the straight alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term "substituted alkenyl" means that the alkenyl group may be substituted with one or more substituents which may be the same or different, each substituent being halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and- Independently selected from the group consisting of S (alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

"Alkynyl" means an aliphatic hydrocarbon group containing one or more carbon-carbon triple bonds, which may be straight or branched, and having from about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; More preferably, there are about 2 to about 4 carbon atoms in the chain. Side chain means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the straight chain alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl and decinyl. The term "substituted alkynyl" means that an alkynyl group may be substituted with one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

"Alkylene" means a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylene include methylene (ie, -CH _2- ), ethylene (ie, -CH ₂ -CH ₂ -CH _2- , -CH (CH ₂ -CH ₃ )-or -CH ₂ -CH ( CH ₃ )-) and propylene.

"Aryl" (sometimes abbreviated as "Ar") means an aromatic monocyclic or polycyclic system having from about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Aryl groups may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Heteroaryl" means an aromatic monocyclic or polycyclic system having from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms, wherein one or more ring atoms is an element other than carbon, eg For example, nitrogen, oxygen or sulfur, alone or a combination thereof. Preferred heteroaryls have from about 5 to about 6 ring atoms. "Heteroaryl" may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined herein. The prefix aza, oxa or thia before the heteroaryl radical name means that at least nitrogen, oxygen or sulfur atoms are each present as ring atoms. The nitrogen atom of the heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thiophenyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl , Thiazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] Thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, Imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.

"Aralkyl" (or "arylalkyl") means an aryl-alkyl- group, where aryl and alkyl are as defined above. Preferred aralkyls include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through alkyl.

"Alkylaryl" means an alkyl-aryl- group, where alkyl and aryl are as previously described. Preferred alkylaryls include lower alkyl groups. Non-limiting examples of suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl. The bond to the parent moiety is through aryl.

"Cycloalkyl" means a non-aromatic mono- or polycyclic system having from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred cycloalkyl rings have from about 5 to about 7 ring atoms. Cycloalkyls may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable polycyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like.

"Halo" means a fluoro, chloro, bromo or iodo group. Fluoro, chloro or bromo are preferred, and fluoro and chloro are more preferred.

"Halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine are preferred, and fluorine and chlorine are more preferred.

"Haloalkyl" means alkyl as defined above, wherein one or more hydrogen atoms on the alkyl are substituted with halo groups as defined above.

"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system that, for example, substitutes a useful hydrogen atom on the ring system. Ring system substituents may be the same or different and each is alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy , Aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulphi Neyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, Y ₁ Y ₂ N-, Y ₁ Y ₂ N-alkyl-, Y ₁ Y ₂ NC (O)-and Y ₁ Y ₂ NSO ₂ -are independently selected from which Y ₁ and Y ₂ may be the same or different. Can be hydrogen, alkyl, aryl and aralkyl Independently selected from the group consisting of. "Ring system substituent" also means a 3 to 7 membered cyclic ring, wherein one or two of the reductions simultaneously represent two ring hydrogen atoms in the aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl ring It may be a heteroatom attached to an aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl ring by substitution. Non-limiting examples are

등을 포함한다.

And the like.

"Cycloalkenyl" means a non-aromatic monocyclic or polycyclic system containing about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, containing one or more carbon-carbon double bonds. Preferred cycloalkenyl rings have from about 5 to about 7 ring atoms. Cycloalkenyl may be the same or different and may be optionally substituted with one or more "ring system substituents" as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting examples of suitable polycyclic cycloalkenyls are norbornylenyl.

"Heterocycloalkenyl" means a non-aromatic monocyclic or polycyclic system having from about 3 to about 10 ring carbon atoms, preferably about 5 to 10 ring carbons, wherein at least one atom in the ring system is an atom other than carbon , For example, nitrogen, oxygen or sulfur atoms, alone or in combination, and contain one or more carbon-carbon double bonds or carbon-nitrogen double bonds. There are no adjacent oxygen and / or sulfur atoms in the ring system. Preferred heterocyclenyl rings have about 5 to about 6 carbon atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least nitrogen, oxygen or sulfur atoms are each present as ring atoms. Heterocycloalkenyl may be optionally substituted with one or more ring system substituents, where "ring system substituents" are as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3, 6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocycloalkenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A non-limiting example of a suitable polycyclic oxaheterocycloalkenyl group is 7-oxabicyclo [2.2.1] heptenyl. Non-limiting examples of suitable monocyclic thiaheterocycloalkenyl rings include dihydrothiophenyl, dihydropiopyranyl and the like.

"Heterocycloalkyl" means a non-aromatic saturated monocyclic or polycyclic system having from about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein at least one of the atoms in the ring system is an element other than carbon, For example, nitrogen, oxygen or sulfur alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocycloalkyls contain from about 5 to about 6 ring atoms. Aza, oxa or thia, prefixed to the heterocycloalkyl root name, means that at least one nitrogen, oxygen or sulfur atom is present as a ring atom, respectively. Heterocycloalkyl may be the same or different on carbon (s) and / or heteroatom (s) and may be optionally substituted with one or more "ring system substituents" as defined herein. Heterocycloalkyl may be optionally oxidized to a nitrogen or sulfur atom to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxanyl, 1,4-dioxa Nil, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.

에서, 2 및 5로 표시한 탄소들에 직접 결합된 -OH는 존재하지 않는다.In the hetero-atom containing ring system of the present invention, not only does not a hydroxyl group exist on the carbon atom adjacent to N, O or S, but also there is no N or S group on the carbon adjacent to another heteroatom. It should be noted. Thus, for example, ring

In, there is no -OH bonded directly to the carbons represented by 2 and 5.

An "arylheterocycloalkyl" is one or two when the aryl and heterocycloalkyl rings share two atoms, and the corresponding shared atoms in the ring may both be carbon, or one or more of the heteroatoms is nitrogen Means a group derived from fused aryl and heterocycloalkyl in which the shared atoms of can be nitrogen.

"Arylcycloalkyl" means a group in which the aryl and cycloalkyl rings are derived from fused aryl and cycloalkyl having two carbon atoms in common. Preferred arylcycloalkyls are those in which aryl is phenyl and cycloalkyl consists of about 5 to about 6 ring atoms. Arylcycloalkyl may be optionally substituted with one or more ring system substituents, where "ring system substituents" are as defined above. Non-limiting examples of suitable arylcycloalkyls include 1,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moiety is through a non-aromatic carbon atom.

"Cycloalkylaryl" means a group derived from fused arylcycloalkyl as defined herein for an arylcycloalkyl group, provided that the bond to the parent moiety is through an aromatic carbon atom.

"Heteroarylcycloalkyl" is a group derived from heteroaryl and cycloalkyl, wherein heteroaryl and cycloalkyl rings have two carbon atoms in common, as defined herein by removing a hydrogen atom from a cycloalkyl moiety. Means. Preferred heteroarylcycloalkyls are heteroaryls of about 5 to about 6 ring atoms and cycloalkyls of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least nitrogen, oxygen or sulfur atoms are each present as ring atoms. Heteroarylcycloalkyl may be optionally substituted with one or more ring system substituents, wherein “ring system substituents” are as defined above. The nitrogen atom of the heteroaryl moiety of heteroarylcycloalkyl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroarylcycloalkyls include 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro Quinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, 1H 4-oxa-1,5-diazanaphthalene-2-onyl, 1,3-dihydroimidazole- [4,5] -pyridine-2-onyl, and the like. The bond to the parent moiety is through a non-aromatic carbon atom.

"Cycloalkylheteroaryl" means a group derived from fused heteroarylcycloalkyl as defined herein for heteroarylcycloalkyl, provided that the bond to the parent moiety is through an aromatic carbon atom.

"Aralkenyl" means an aryl-alkenyl-group in which aryl and alkenyl are as previously described. Preferred aralkenyls contain lower alkenyl groups. Non-limiting examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl. Binding to the parent moiety is through alkenyl.

"Aralkynyl" means an aryl-alkynyl- group in which allyl and alkynyl have been previously described. Preferred aralkynyl contains a lower alkynyl group. Non-limiting examples of suitable aralkynyl groups include phenacetylenyl and naphthylacetylenyl.

"Heteroaralkyl" (or "heteroarylalkyl") means a heteroaryl-alkyl- group where heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain lower alkyl groups. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2- (furan-3-yl) ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through alkyl.

"Heteroaralkenyl" means a heteroaryl-alkenyl-group in which heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain lower alkenyl groups. Non-limiting examples of suitable heteroaralkenyl groups include 2- (pyridyl-3-yl) ethenyl and 2- (quinolin-3-yl) ethenyl. Binding to the parent moiety is through alkenyl.

"Heteroarlkynyl" means a heteroaryl-alkynyl-group in which heteroaryl and alkynyl have been previously described. Preferred heteroaralkynyl contains lower alkynyl groups. Non-limiting examples of suitable heteroaralkynyl groups include pyrid-3-ylacetylenyl and quinolin-3-ylacetylenyl. Binding to the parent moiety is through alkynyl.

"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyl contains lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" refers to HC (O)-, alkyl-C (O)-, alkenyl-C (O)-, alkynyl-C (O)-, cycloalkyl-C ( O)-, cycloalkenyl-C (O)-or cycloalkynyl-C (O)-group. Binding to the parent moiety is via carbonyl. Preferred acyls contain lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl.

"Aroyl" means an aryl-C (O)-group in which the aryl group is as previously described. Binding to the parent moiety is via carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl.

"Heteroaroyl" means a heteroaryl-C (O)-group in which the heteroaryl group is as previously described. Non-limiting examples of suitable groups include nicotinoyl and pyrrole-2-ylcarbonyl. Binding to the parent moiety is via carbonyl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. Binding to the parent moiety is through ether oxygen.

"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. Binding to the parent moiety is through ether oxygen.

"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. Binding to the parent moiety is through ether oxygen.

"Alkyl amino" means an -NH ₂ or -NH ₃ ⁺ group substituted by alkyl groups as defined above, at least one of the hydrogen atoms on the nitrogen.

"Arylamino", means an -NH ₂ or -NH ₃ ⁺ group substituted with an aryl group as defined above at least one of the hydrogen atoms on the nitrogen.

"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio. Binding to the parent moiety is through sulfur.

"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. Binding to the parent moiety is through sulfur.

"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkylthio groups are benzylthio. Binding to the parent moiety is through sulfur.

"Alkoxycarbonyl" refers to an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. Binding to the parent moiety is via carbonyl.

"Aryloxycarbonyl" refers to an aryl-O-C (O)-group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. Binding to the parent moiety is via carbonyl.

"Aralkoxycarbonyl" means an aralkyl-O-C (O)-group. Non-limiting examples of suitable aralkoxycarbonyl groups are benzyloxycarbonyl. Binding to the parent moiety is via carbonyl.

"Alkylsulfonyl" means an alkyl-S (O ₂ )-group. Preferred groups are those in which the alkyl group is lower alkyl. Binding to the parent moiety is through sulfonyl.

"Alkylsulfinyl" means an alkyl-S (O)-group. Preferred groups are those in which the alkyl group is lower alkyl. Binding to the parent moiety is through sulfinyl.

"Arylsulfonyl" means an aryl-S (O ₂ )-group. Binding to the parent moiety is through sulfonyl.

"Arylsulfinyl" means an aryl-S (O)-group. Binding to the parent moiety is through sulfinyl.

The term "cycloalkylene" refers to substitution by a cyclic group on the same carbon atom in an alkylene group. Non-limiting example

를 포함한다.

It includes.

It should be noted that any heteroatoms having unfilled valences in the context, schemes, examples, and tables herein are assumed to be bonded to a sufficient number of hydrogen atoms to satisfy the valences.

When a functional group is named “protected” in a particular compound, it means that when the compound is subjected to a reaction, the group is in a modified form that prevents undesirable side reactions at the protected site. Suitable protection groups are described, for example, only in reference to standard textbooks such as TW Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York, which are hereby incorporated by reference in their entirety. It will also be appreciated by those skilled in the art.

Specific variables (e.g. aryl, heterocycle, R ³ Etc.) occur more than once in a particular construct or formula (I), its definition at each occurrence is independent of its definition at every other occurrence.

With respect to the number of residues (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there may be many chemically acceptable residues, and Determination of the number of such residues is within the knowledge of those skilled in the art.

As used herein, the term "composition" is intended to include not only products comprising a particular amount of a particular component, but also certain products produced directly or indirectly from a combination of particular amounts of a particular component.

은 예를 들면, (R)- 및 (S)- 입체화학을 함유하는 가능한 이성체 각각 또는 이들의 혼합물을 일반적으로 나타낸다. 예를 들어, Wave line as a bond

Generally represents each or a mixture of possible isomers containing, for example, (R)-and (S) -stereochemistry. E.g,

는

를 둘 다 함유함을 의미한다.

Is

It means that both contain.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. As used herein, the term “prodrug” refers to a compound that is a drug precursor that is chemically converted by metabolic or chemical processes upon administration to a patient to produce a compound of Formula I or a salt and / or solvate thereof. The discussion of prodrugs is described in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.

"Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonds, including hydrogen bonds. In certain instances, solvates may be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvates" include both solution-phase and separable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate, and the like. "Hydrate" is a solvate in which the solvent molecule is H ₂ O.

By "effective amount" or "therapeutically effective amount" is meant to describe the amount of a compound or composition of the present invention effective to produce the desired therapeutic effect in a suitable patient by inhibiting gamma-secretase.

Compounds of formula I also form salts within the scope of the present invention. References herein to compounds of formula (I) are understood to include references to salts thereof unless otherwise indicated. As used herein, the term “salt (s)” refers to acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. In addition, when the compound of formula (I) contains basic residues such as, but not limited to, pyridine or imidazole, and acidic residues such as, but not limited to, carboxylic acids, zwitterions (“internal salts”) are formed. And may be included within the term "salt (s)" as used herein. Pharmaceutically acceptable (eg non-toxic, physiologically acceptable) salts are preferred, although other salts may also be useful. Salts of compounds of formula (I) can be formed, for example, by reacting compounds of formula (I) with an equivalent amount of acid or base in the same medium in which the salt precipitates or in an aqueous medium and then lyophilized.

Exemplary acid addition salts include acetate, alginate, adipate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentaneprop Cypionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 Hydroxyethanesulfonate, lactate, malate, methanesulfonate, 2-naphthalenesulfonate, nacotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate , Pivalate, propionate, salicylate, succinate, sulfate, sulfonate (e.g. Those mentioned), tartrate, thiocyanate, toluenesulfonate (also including also known as tosylates), undecanoate. In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are described, for example, in S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-. 19; P. Gould, Intemational J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C., on their website), the disclosures of which are incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as chaselle and magnesium salts, salts with organic bases such as organic amines, for example Benzatin, dicyclohexylamine, hydravamin (formed with N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t -Butyl amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide, dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfate, long chain halides Examples: quaternized with agents such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide), aralkyl halides (eg benzyl and phenethyl bromide) and others.

All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the present invention and all acid and base salts are considered equivalent to the free form of the corresponding compound for the purposes of the present invention.

Compounds of the invention and carboxylic acid groups may form pharmaceutically acceptable esters with alcohols. Examples of suitable alcohols include methanol and ethanol.

Likewise, the compounds of the invention and the hydroxyl groups can form pharmaceutically acceptable esters with carboxylic acids, such as acetic acid.

The compounds of formula (I), and salts, solvates and prodrugs thereof, may exist in their tautomeric forms (eg amides or imino ethers). All such tautomeric forms are contemplated herein as part of the present invention.

Compounds of the invention (salts, solvates and prodrugs of the present compounds), including enantiomeric forms (which may also be present in the absence of asymmetric carbon), rotamers, atropisomers and diastereomers All stereoisomers (including those) (eg, geometric isomers, optical isomers, etc.), for example, those which may be present due to asymmetric carbons on various substituents, are considered to be within the scope of the present invention. Individual stereoisomers of the compounds of the invention may be substantially free from, for example, other isomers, or may be mixed, for example, as racemates or all other or other selected stereoisomers. The chiral center of the present invention may have an S or R configuration as defined by the IUPAC 1974 Commission. The use of the terms “salts”, “solvates”, “prodrugs” and the like is equivalent to the salts, solvates and prodrugs of the enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the compounds of the invention. It is intended to be applied.

Compounds of formula (I), and polymorphic forms of salts, solvates and / or prodrugs of compounds of formula (I) are also intended to be included in the present invention.

In the specification and / or claims herein, all formulas, compounds, residues or chemical descriptions having unsatisfactory valences are assumed to have the hydrogen atom (s) necessary to satisfy the valences.

Those skilled in the art describe the disease and condition resulting from the abnormal action of neurons, including the term "neurodegenerative disease", a generally acceptable medical meaning and neuronal death and abnormal release of neurotransmitters and neurotoxics. . Examples thereof also include all diseases resulting from abnormal levels of beta amyloid protein. Examples of such diseases include, but are not limited to Alzheimer's disease, aging-related dementia, central or systemic amyloidosis, genetic cerebral hemorrhage with amyloidosis, and Down syndrome.

E.g,

와 같은 환 시스템내 도시된 선은, 나타낸 선(결합)이 치환가능한 환 탄소 원자의 특정의 치환체에 부착될 수 있음을 나타낸다.

Lines shown in a ring system, such as, indicate that the indicated line (bond) may be attached to a particular substituent of substitutable ring carbon atoms.

As is well known in the art, a bond depicted from a particular atom in the absence of a residue shown at the end of the bond represents a methyl group bound through a bond to that atom. For example:

Compounds of formula (I) can be prepared by methods known in the art and by the following methods.

The pharmaceutical composition may comprise one or more compounds of formula (I). To prepare pharmaceutical compositions from the compounds described herein, the inert, pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may comprise about 5 to about 95% of the active ingredient. Suitable solid carriers are known in the art and are, for example, magnesium carbonate, magnesium stearate, talc, sugars or lactose. Tablets, powders, cachets and capsules can be used in solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions are described in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. have.

Liquid form preparations include solvents, suspensions and emulsions. As an example, mention may be made of parenteral water for injection or water-propylene glycol solutions, or additions of sweetening and whitening agents for oral solvents, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol formulations suitable for inhalation may include solids and solvents in powder form, which may be combined with pharmaceutically acceptable carriers such as inert compressed gas (eg nitrogen).

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solvents, suspensions or emulsions.

Compounds of the invention can also be delivered transdermally. Such transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in transdermal patches of the matrix or reservoir type as are conventional in the art for this purpose.

The pharmaceutical formulation is also present in unit dosage form. In this form, the formulation is subdivided into unit doses of suitable size, containing suitable amounts of the active ingredient, eg, an amount effective to achieve the intended purpose.

The amount of active compound in the unit dose of the formulation is about 0.01 mg to about 1000 mg, preferably about 0.01 mg to about 750 mg, more preferably about 0.01 mg to about 500 mg, most preferably about 0.01 mg, depending on the particular application. To about 250 mg can be varied or adjusted.

The actual dosage used can be determined according to the requirements of the patient and the severity of the disease to be treated. Determination of the appropriate dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dose may be administered in several portions as needed during the treatment period.

The dosage and frequency of administration of the compounds of the invention and / or pharmaceutically acceptable salts thereof will be adjusted at the discretion of the attending physician, taking into account such factors as the age, condition and size of the patient as well as the severity of the condition to be treated. . For oral administration, the recommended daily dosage regimen is from about 0.04 mg / day to about 4000 mg / day in one to four doses.

Representative compounds of the invention are, but are not limited to, compounds of Examples 1-24.

Compounds of formula (I) can be prepared by various methods known in the art and by the following methods.

Scheme 1A: R ² In-( C ₀ - C ₁₃ ) Alkylene  Formation of chains

Reaction stage

(a) NaOH / H ₂ O / EtOH or THF / LiOH / H ₂ O

(b) (C (O) Cl) ₂ / DCM / DMF (cat.) or SOCl ₂ / solvent

(c) diazomethane

(d) Ag ⁺ / H ₂ O / organic co-solvent

(e) LAH

(f) DIBAL

(g) RuCl ₃ (cat.) / NaIO ₄

(h) diborane

(i) Dess-Martin or Swern oxidation conditions [see, eg, Dess, DB, Martin, J. C, J. Org. Chem., 1983, vol. 48, beginning at p. 4155; Omura, K., Swern, D. Tetrahedron, 1978, vol. 34, beginning at p. 1651), both of which are incorporated herein by reference in their entirety.

(j) methoxymethyltriphenylphosphonium bromide (or chloride) / base

(k) H ₃ O ⁺

(l) NaClO ₂

Esters I can be prepared, for example, by the methods described in US Patent Application No. 10 / 358,898 (Compound 19), incorporated herein by reference in its entirety. Compound I may be subjected to direct hydrolysis (ie step (a)) or in a two step process, wherein ester I is reduced to alcohol VI in step (e), followed by oxidation of VI in step (g) ] To carboxylic acid II. Carboxylic acid side chains of compound II are described, for example, in W. E. Bachmann, Org. React. 1, 38-39, 1942 (incorporated herein by reference in its entirety), to be homologized via intermediates III and IV using Arndt-Eistert synthesis. Can provide the homologized carboxylic acid V. The carboxylic acid side chain of compound V is further added by repeating the anand-ester synthesis step (i.e., using compound V as starting material and then applying steps (b), (c), and (d) successively). Can be homologized. By repeating the Andand-Ester synthesis step in this manner, an alkylene chain of a specific desired length can be prepared (for example as in Scheme 1B below).

Homologization can also be carried out by reducing compound I to DIBAL (ie step (f)) or by preparing aldehyde VII by oxidizing alcohol VI in step (i). Alcohol VI can be prepared by reducing compound I in step (e) or by reducing compound II in step (h). The aldehyde VII can then be reacted with enol ether VIII under a Wittig reaction condition, which can in turn be hydrolyzed to aldehyde IX (eg step (k)).

In another synthesis of aldehyde IX, alcohol VI may first be converted to iodide, for example by combining triphenylphosphine with iodine (Scheme 1 Aa). Subsequent conversion of iodide and cyanide and reduction of the nitrile obtained with DIBAL can provide aldehyde IX.

Scheme 1 Aa : Another Synthesis of Aldehyde IX

Reaction stage

(aa) PPh ₃ / I ₂

(bb) n-Bu ₄ NCN

(cc) DIBAL

The same cycle of homologation using the Beatig reaction conditions can be repeated starting with aldehyde IX, or further homologues by oxidizing aldehyde IX to the corresponding acid V and repeating the Arnant-Ester synthesis step as discussed above. To give Compound X as in Scheme 1B below.

Scheme 1B: Carboxylic acid Branched  Repeated Homologization

Of course, starting material I in Scheme 1A is just one of a number of possible starting materials that can be used to prepare the compounds according to general formula I. For example, the homologation reaction conditions described in Schemes 1A and 1B are not limited to starting materials (eg Compound I) in which the indices n and o are both zero.

Scheme 2A: R ² In Cyclopropylene Residue  formation

Reaction stage

(m) SOCI ₂ / MeOH

(n) Tebebe reagent

(o) H ₃ O ⁺

(p) t-BuSiMe ₂ -OS (O ₂ ) CF ₃ / Et ₃ N

(q) MCPBA

(r) Ph ₃ P ⁺ CH ₃ Cl ^- / BuLi

(s) tetrabutylammonium fluoride

(t) Et ₂ Zn / ICH ₂ Cl

(u) RuCl ₃ / NaIO ₄

Carboxylic acid X (eg prepared according to Scheme 1B) can be transferred to methyl ester XI in step (m), and then the methyl ester can be converted to allyl acid alcohol XVII by a number of known methods. For example, methyl ester Xl is converted to enol ester XII by olefining with the Thebe reagent in step (n). See S.H. Pine et al, Org. Synth., 69, 72-79, 1990, and then hydrolytically convert to ketone XIII in step (o). Subsequently, ketone XIII is converted to silyl enol ether XIV in step (p) and oxidized in step (q) (see N. Yamamoto, M. Isobe, Tetrahedron 1993, 49 (30) incorporated herein by reference. ), 6581-6590) t-butyldimethylsilyloxy ketone XV. The ketone XV is bitig olefined in step (r) to afford compound XVI. In step (s) the silyl protecting group of compound XVI is cleaved to give allyl acid alcohol XVII, which is cyclopropane in step (t) to give alcohol XVIII. Thereafter, alcohol XVIII is oxidized to carboxylic acid XIX in step (u). Further homologation of the carboxylic acid, if necessary, is carried out as described above in Scheme 1B to afford compound XX.

Scheme 2 Aa : Another Synthesis of Ketone XIII

Reaction stage

(dd) HN (OMe) Me / i-PrMgCl

(ee) MeMgBr

(ff) DIBAL

(gg) Dess-Martin periodinane

Ester XI can be converted to N-methyl-N-methoxyamide in step (dd), which can be further reacted with methyl Grignard reagent (ee) to give ketone XIII. It is also possible to convert aldehydes, for example by reducing DIBALFH. The aldehyde can be reacted with methyl Grignard reagent to give a secondary alcohol, which can be oxidized to a ketone in step (gg).

Scheme 2 Ab : Ketone XIII Alcohol XVII Another variant of

Reaction stage

(hh) LDA / 2- [ N, N- bis (trifluoromethylsulfonyl) amino] -5-chloropyridine

(ii) MeOH / CO / Pd (PPh ₃ ) ₄ (cat)

(jj) DIBAL

Ketone XIII can be converted to enol triflate in step (hh). The enol triflate may then be carbonylated with carbon monoxide to provide the conjugated ester in step (ii). Reduction of the ester in step jj is performed using, for example, excess DIBAL to give alcohol XVII.

Scheme 2B: R ² In-( C ₃ - C ₆ ) Cycloalkylene Residue  formation

                   Hal = I, Br, Ts

Cycloalkylene moieties other than cyclopropyl can be formed, for example, by the method of formula 2B when the R ² side chain has a carbonyl group located after the methylene group. For example, compound XXI can be reacted with bis-halide or bis-tosylate in the presence of a suitable base to form cycloalkylene ketone XXII. Those skilled in the art will recognize that XXI is simply a special case of Xl, where c is one or more.

Likewise, starting materials XX and XXI in Schemes 2A and 2B are not the only possible starting materials that can be used to prepare compounds according to formula I in Schemes 2A and 2B, respectively. For example, the ring closure reaction conditions described in Schemes 2A and 2B are not limited to starting materials, where the indices n and o are both 0 (eg, compounds XX and XXI).

Scheme 3: R ² In-( C ₃ - C ₆ ) Cycloalkylene  Formation and Alkylene  Combination of chain growth

Those skilled in the art will appreciate that alkylene chain growth processes (e.g., Schemes 1A and 1B) and cycloalkylene formation processes (e.g., Schemes 2A and 2B) can be combined in various ways to form the R ² side chains of the compounds according to formula (I). It will be appreciated that various combinations of alkylene and cycloalkylene moieties can be provided. For example, as shown in Scheme 3, compound I is homologized to extend the alkylene chain to the desired extent, then forms a cycloalkylene moiety, and then, if necessary, further homologs of alkylene to compound XXIII can be obtained.

Scheme 4: R ² -C (O)-, -S (O)-, and -S ( O ₂ )- Residue  formation

Carboxylic acid X or XX or XXIII can be reduced to the corresponding alcohol XXIV by reaction with borane. The alcohol XXIV can then be reacted with suitable reagents such as mesyl chloride (ie methane sulfonyl chloride) and triethylamine to give a compound having a suitable leaving group, for example mesylate XXV. The mesylate group can then be replaced with potassium thioacetate to provide the thioacetic acid ester XXVI, which is hydrolyzed (eg sodium methoxide in methanol) to give thiol XXVII. Oxidation of thiol XXVII with sulfonyl chloride provides sulfonyl chloride XXVIII (Youn, J.-H .; Herrmann, R .; Synthesis 1987 (1), 72), incorporated herein by reference in its entirety. do. Oxidation of thiol XXVII with excess chlorine provides sulfonyl chloride XXIX (Barnard, D .; Percy, E. J .; J Chem Soc 1962, 1667, incorporated herein by reference in its entirety). In addition, the reaction of oxalyl chloride (optionally using the catalytic DMF present) with carboxylic acid X or XX or XXIII provides the acyl chloride XXX.

Those skilled in the art will appreciate that the reactions described in Scheme 4 above can be carried out using other carboxylic acid compounds, although not limited to the particular starting materials shown.

Scheme 5: R ² Y Residue  Introduction

Residue Y of R ² may be prepared from a suitable sulfinyl chloride, sulfonyl chloride or acyl chloride (eg prepared as described in Scheme 4) with a suitable HY, optionally in the presence of an organic base such as triethylamine. It can introduce | transduce by making it react. For example, compounds XXVIII, XXIX, and XXX may react with HY (eg, where HY is piperidine, pyrrolidine, substituted piperidine, substituted pyrrolidine, etc.) and a compound according to Formula I XXXI, XXXII, and XXXIII can be formed. Compound XXXIII also contains carboxylic acid X, XX, or XXIII for amide formation conditions, such as, for example, Humphrey, JM, Chamberlin, R., Chem. Rev., 1997, vol. 97, pp. 2243-2266 can be prepared by coupling with HY using the conditions described.

Scheme 6: another formation of the piperidine core

In addition, the piperidine “core” of the compounds of the invention can be prepared by the cycloaddition reaction between alkene XXXVII and imine XXXIX. Alkenes XXXVII can be prepared by bittig reacting aldehyde XXXIV with phosphoran XXXV to form α, β-unsaturated ketone XXXVI. Enol ether XXXVII can be formed by trapping the enolate of XXXVI with TBSCl. The resulting TBS enol ether XL can be hydrolyzed with piperidinone XLI using mild acid. Ketone XLI can be reduced to alcohol XLII. Those skilled in the art will recognize that ketone XLI and alcohol XLII are further modified to yield compounds XLIII and XLIV, which represent a subset of formula I claimed herein.

Specific examples of the preparation of compounds according to formula (I) are described below.

Produce Example  One

Methyl ester 1 was prepared in a similar manner to the preparation of ethyl ester 5 of Example 173 of US Pat. No. 10 / 358,898 as follows.

Preparation of Methyl Ester 1

Step 1: To a cooling (6 ° C.) mixture of 6-bromopicolinic acid (40.0 g, 198 mmol) in methanol (750 ml) anhydrous thionyl chloride (58 mL) was added slowly. All 6-bromopicolinic acid dissolved while gradually raising the temperature to 34 ° C. The mixture was refluxed for 5 hours. The solvent was removed in vacuo and the residue was dissolved in 2 L of ethyl acetate and washed with 2 L of saturated sodium carbonate. The aqueous phase was reextracted with 1.5 L ethyl acetate. The combined organic phases were washed with 1.5 L brine, dried over anhydrous MgSO ₄ , filtered and concentrated to dryness to afford methyl 6-bromopicolinate (34.0 g) as off-white solid.

Step 2: Methyl 6-bromopicolinate (43.8 g, 202.8 mmol) was added 3,5-difluorophenylboronic acid (40.6 g, 263.9 mmol) in toluene (572 mL) and ethanol (286 ml), tetrakis Heated at 80 ° C. for 16 h in the presence of (triphenylphosphine) palladium (23.5 g, 20.3 mmol) and sodium carbonate (45.2 g, 426 mmol). The mixture was cooled to room temperature and concentrated on rotovap to remove solvent. The obtained residue was dissolved in 1.3 L of DCM and washed twice with 800 mL of water. The combined aqueous phases were extracted with 500 mL of DCM. The organic phases were combined and then washed with brine, dried and concentrated to give approximately 90 g of dark semisolid material. The material was mixed with 280 mL of DCM and loaded onto a 1.5 L silica gel column (pre-filled with hexanes) and eluted with a gradient of 10-30% ethyl acetate in hexanes. After evaporating the solvent and drying, 45.6 g of an off-white product were obtained.

Step 3: Under a hydrogen atmosphere, a solution (45.6 g, 183.0 mmol) of the product from step 2 in methanol (2.4 L) and glacial acetic acid (600 mL) was stirred for 72 h in the presence of platinum oxide (12.5 g). Thereafter, the reaction mixture was purged with nitrogen and the reaction mixture was filtered and then concentrated in vacuo. The obtained residue was dissolved in water, treated with saturated sodium carbonate and extracted with DCM. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a pale yellow foam (44.5 g).

Step 4: The solution of the product of step 3 in pyridine (300 mL) (44.5 g, 174 mmol) was treated with 4-chlorobenzenesulfonylchloride (110 g, 523 mmol). The mixture was heated at 60 ° C. for 4 h, cooled to rt and concentrated in vacuo, and the residue obtained was flash-chromatated over silica gel (eluted with 10% ethyl acetate in hexanes) to 70.5 g of methyl ester. 1 was provided as a white powder.

Scheme 1

(즉, 규조토 여과제)를 사용하여 여과시켰다. 유기 용매를 증발시키고 잔사를 섬광 크로마토그래피(용매로서 헥산 중의 10 내지 15%의 에틸 아세테이트를 상용하는 실리카 겔 200g)로 처리하여 대략 6.0g의 엔올 에테르 2를 수득하였다. Step 1: To a solution of 7.0 g (16.3 mmol) of ester 1 in 20.0 mL of dry THF was added dropwise at 0 ° C., 50.0 mL of approximately 1 M Tebebe reagent in toluene, followed by dropwise addition of 8.0 mL of pyridine. The mixture was stirred at ambient temperature for 3 hours and quenched by cannulation the mixture into approximately 200 g of crushed ice. Thereafter, approximately 200 mL of DCM was added and the mixture was stirred for 30 minutes. The organic phase was then separated from the aqueous phase and the inorganic precipitate. The aqueous phase was reextracted with DCM and the organic phases combined. The combined organic phases are then dried over anhydrous sodium sulfate overnight and then the solid is celite

(Ie diatomaceous earth filter). The organic solvent was evaporated and the residue was treated with flash chromatography (200 g of silica gel with 10-15% ethyl acetate in hexane as solvent) to yield approximately 6.0 g of enol ether 2.

Step 2: To a mixture of 1.0 g of enol ether 2 in 20.0 mL of acetone and 5 mL of DCM (added for solubility), 0.5 mL of TFA was added. The mixture was stirred for 45 minutes, during which time the precipitate came out of solution. The volatile components of the mixture were removed to give a solid residue. The solid residue was redissolved in DCM and washed with 50% saturated aqueous NaHCO ₃ . The solution was then dried, concentrated and passed through a 10 g silica gel plug using a mixture of 10% DCM, 10% EtOAc and 80% hexane as solvent to afford 900 mg of ketone 3.

Step 3: To a mixture of 10.05 g (24.3 mmol) ketone 3 in 140 ml DCM, 4.92 g (48.6 mmol) triethylamine and 8.00 g (30.4 mmol) tert-butyldimethylsilyltrifluoromethanesulfonate Was added. The mixture was stirred overnight, washed with ice-cold water, brine (saturated aqueous NaCl), dried over anhydrous sodium sulfate, concentrated and exposed to high vacuum at 60 ° C. over 2 hours to give 13.9 g of crude TBS enol ether 4 Obtained.

Step 4: To a solution of 13.9 g of crude TBS enol ether 4 in 100.0 mL of DCM was added dropwise over 1 hour 100.0 mL of DCM (Technical MCPBA containing 57-86% active material). The mixture was stirred for an additional 25 minutes. Since the reaction was incomplete by NMR analysis of the treated portion of the reaction mixture (using the following treatment conditions), an additional 1.0 g of MCPBA in 10 mL of DCM was added and the mixture was stirred for an additional 20 minutes. The mixture was then washed with saturated aqueous NaHCO ₃ , and brine, dried over anhydrous sodium sulfate and concentrated. The product was purified by chromatography on 120 g silica gel using 10% EtOAc in hexane as solvent to yield 9.3 g ketone 5.

Step 5: To a suspension of 3.5 g (9.9 mmol) methyltriphenylphosphonium bromide in THF (20 mL) at -40 ° C. was added 3.8 mL (9.6 mmol) of 2.5 M n-butyllithium in hexane. The suspension was stirred at −40 ° C. for 5 minutes and then at 0 ° C. for 25 minutes. Then 2.0 g (3.7 mmol) ketone 5 in dry THF (10.0 mL) was slowly added to the suspension. The resulting reaction mixture was stirred at 0 ° C. overnight. The reaction mixture was quenched with water, extracted with EtOAc, washed with water and brine and dried over anhydrous sodium sulfate. The concentrated product was purified by chromatography using 0-15% gradient ethyl acetate in hexanes to give 950 mg of alkene 6.

Step 6: To a mixture of 1.0 g (2.0 mmol) of alkene 6 in THF (32.0 ml) was added 4.0 mL (4.0 mmol) of TBAF (1M in THF). The mixture was then stirred for 2 hours. TLC analysis of the mixture (20% EtOAc / hexanes; silica stationary phase) indicated the reaction was complete, indicating that a more polar product was obtained. The solvent was evaporated from the mixture and the obtained residue was partitioned between DCM and water. The organic and aqueous phases were separated and the organic phase was washed with water and brine, dried over anhydrous magnesium sulphate and concentrated to afford 1.0 g of crude alcohol 7.

Step 7: 1.0 mL (14 mmol) of chloroiodomethane was added dropwise to a mixture of 20.0 mL of DCM in hexane and 14.0 mL (14 mmol) of 1M diethylzinc at 0 ° C. The mixture was stirred at 0 ° C. for 10 minutes, then a solution of 1.0 g of Alcohol 7 in 20.0 mL of DCM was added dropwise. The mixture was stirred at ambient temperature for 3.5 hours. The reaction mixture was quenched with aqueous NH ₄ Cl (20%), extracted with DCM and washed with water and brine. The organic and aqueous phases were separated and the organic phase was dried over anhydrous magnesium sulfate and concentrated. The product was purified by silica gel chromatography using 0-25% gradient ethyl acetate in hexanes to yield 550 mg of cyclopropylmethanol 8.

Step 8: To 550 mg (1.24 mmol) of Compound 8 in a mixture of 4.0 mL of CCl ₄ and 4.0 mL of CH ₃ CN was added a solution of 1.1 g (4.98 mmol) of NaIO ₄ in 6.0 mL of water, followed by 25 mg (0.12). mmol) RuCl ₃ .H ₂ O was added. The dark brown mixture obtained was stirred overnight and then partitioned between DCM and water. The aqueous and organic phases were separated and the aqueous phase was reextracted with DCM. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to afford 560 mg of crude acid 9.

Step 9: To a solution of 560 mg (1.19 mmol) of acid 9 in DCM (18.0 ml) was added 0.625 mL (7.15 mmol) of oxalyl chloride. The mixture was stirred for 2.5 hours. The solvent was removed and the residue obtained was placed under high vacuum for 5 hours to yield 550 mg of acyl chloride 10.

Step 10: (a) Preparation of diazomethane. In a 250 mL flask, 14.0 mL of 5M NaOH and 67.0 mL of ether were added. The mixture was cooled to -5 ° C (internal temperature) using an ice / NaCl bath. 3.0 g (20.4 mmol) of 1-methyl-3-nitro-1-nitrosoguanidine were added in portions with stirring. The yellow ether layer was decanted into the pre-cooled flusk and dried over several KOH pellets. The resulting diazomethane solution was kept in a loosely covered flask, cooled with ice / NaCl, and used within 10 minutes after generation.

(b) The diazomethane solution obtained in step (a) was added to a pre-cooled (0 ° C.) solution of 550 mg of acyl chloride in 10.0 mL of THF. The mixture was left overnight at ambient temperature. The reaction mixture was concentrated in vacuo at room temperature to approximately 15 mL, then diluted with 100 mL of DCM, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous sodium sulfate and concentrated in vacuo at a temperature of 30 ° C. The concentrated product was passed through a 5 g silica gel plug using 30% ethyl acetate in hexanes to yield 300 mg of diazoketone 11.

Step 11: A mixture containing 250 mg of diazoketone 11, 8.0 mL of dioxane, 4.0 mL of water and 15 mg of silver benzoate was heated at 75 to 80 ° C. for 2 hours. The reaction mixture was then partitioned between DCM and water and the aqueous phase was reextracted 5 times with DCM. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated product was then passed through a 5 g silica gel plug using 0-5% gradient methanol in DCM. Further purification by reverse phase chromatography (C-4 phase, water-acetonitrile, 0.1% TFA) afforded 140 mg of acid 12.

Step 12: To a mixture of 15 mg (0.032 mmol) acid 12 in 1.0 mL DCM was added 5.2 mg HOBT, 7.3 mg EDCl, followed by 5 mg 2-piperazin-1-yl-ethanol and 7 μL triethylamine. Was added. The mixture was stirred for 3 hours and washed with water. The organic phase was then loaded onto a preparative TLC plate (silica gel) using 5% MeOH in DCM as solvent and then repurified by reverse phase HPLC (C-4 column, acetonitrile-water) to 10 mg. The compound of Example 1 was obtained.

Example  One:

Example  Preparation of 2-6 Compounds

The compounds of Examples 2 to 6 can then be reacted by reacting acid 12 with a suitable cyclic amine (ie, rather than using 2-piperazin-1-yl-ethanol) under similar conditions as described in step 12 above. Prepared. Thus, for example, the compound of Example 2 was prepared by reacting acid 12 with piperidine rather than 2-piperazin-1-yl-ethanol.

Example  Preparation of 7-18 Compounds

The compounds of Examples 7 to 18 below react the acid 9 or acyl chloride 10 prepared as described above with a suitable amine, optionally in the presence of a base such as pyridine or triethylamine and also optionally in the presence of a catalyst such as dimethylaminopyridine. By Humphrey, JM, Chamberlin, R., Chem. Rev., 1997, vol. 97, pp. 2243-2266].

Example  Preparation of 19 Compounds

Example  19

Scheme 2

Step 1: 0.434 mL (3.12 mmol) of triethylamine was added to 690 mg (1.56 mmol) of Compound 8 in DCM (15.0 mL) at 0 ° C., followed by the dropwise addition of 0.145 mL (1.87 mmol) of methanesulfonyl chloride. . The mixture was stirred for 2 hours and washed with aqueous NaHCO ₃ and brine. The organic phase and the aqueous phase were separated and the organic phase was then dried over anhydrous MgSO ₄ . Thereafter, the solvent was evaporated to yield 850 mg of crude Compound 13.

Step 2: A mixture of 850 mg (1.64 mmol) of compound 13 and 373 mg (3.27 mmol) of potassium thioacetate was stirred at 55 ° C. for 6 hours in 10.0 mL of DMF. Thereafter, the solvent was evaporated and the obtained residue was partitioned between DCM and water. The organic phase was washed with water and brine. Thereafter, the solvent was evaporated and the residue obtained was purified by silica gel column chromatography using DCM of 0-100% gradient in hexane. 760 mg of thioacetate ester 14 were obtained.

Step 3: To a mixture of 760 mg (1.52 mmol) of thioacetate ester 14 in degassed MeOH (15 mL) and DCM (1 mL, added for solubility) was added 21 mg (0.38 mmol) of sodium methoxide. The mixture was heated to 55 [deg.] C. under nitrogen for 40 minutes and then the solvent was evaporated. The obtained residue was partitioned between DCM and water and the aqueous phase was reextracted three times with DCM and once with ethyl acetate. The organic phases were combined and then washed with saturated aqueous NH ₄ Cl and brine and the solvent was evaporated to form a residue. 670 mg of crude thiol 15 was obtained and used without further purification in step 4.

Step 4: Chlorine gas was bubbled into a solution of 90 mg thiol 15 in 2 mL AcOH / water (50/1 volume) for 10 minutes. The solvent was then evaporated. The residue was partitioned between DCM and water, then the organic and aqueous phases were separated. The organic phase was washed with aqueous NaHCO ₃ , dried and the solvent was evaporated to afford crude sulfonyl chloride 16.

Step 5: Crude sulfonyl chloride 16 was dissolved in 1.5-2.0 mL of pyridine. This solution was treated with 92 mg of 4-piperidinopiperidine and then heated at 60 ° C. overnight. Thereafter, the reaction mixture was partitioned between saturated aqueous NaHCO ₃ and DCM, and the organic phase was washed with water and brine and dried. Thereafter, the organic and aqueous phases were separated and the solvent was evaporated from the aqueous phase. Thereafter, the obtained residue was purified by preparative TLC using 5% MeOH / DCM as a solvent to obtain 47 mg of the compound of Example 19.

Example 19: ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.89 (2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.04 (2H, d, J = 7.3 Hz) , 6.73 (1H, m), 5.18 (1H, s), 4.71 (1H, dd, J = 2.9, 7.3 Hz), 3.99 (1H, d, J = 13.2 Hz), 3.86 (2H, d, J = 14.0 Hz), 2.83 (1H, dt, J = 2.2, 12.0 Hz), 2.71 (1H, dt, J = 2.2, 12.0 Hz), 2.54-2.35 (5H, ser m), 2.17 (1H, d, J = 14 .0 Hz), 2.20 (1H, m), 1.88 (1H, m), 1.72-1.55 (7H, ser m), 1.47-1.30 (5H, ser m), 1.14 (3H1 m), 0.58 (1H, m ), 0.28 (1H, m), 0.00 (1H, m). LCMS (ES): retention time 4.01 min; m / z = 656.4 (M + H) ⁺

Example  Preparation of 20 to 24 Compounds

The compounds of Examples 20-24 were prepared by a method similar to that used to prepare the compound of Example 19, except that the appropriate amine was used instead of 4-piperidinopiperidine in step 5. That is, for example, the compound of Example 21 was prepared using N-methylpiperazin instead of 4-piperidinopiperidine.

Example  Preparation of 25 Compounds

Scheme 3

Step 1: To 110 mg (0.25 mmol) of alcohol 8 in 15 mL of DCM was added 127 mg (0.3 mmol) of death-martin periodinan followed by 31 mg (0.37 mmol) of NaHCO ₃ . Thereafter, the reaction mixture was stirred at room temperature for 2 hours and quenched with 0.4 g sodium thiosulfate in saturated NaHCO ₃ . The product was extracted with DCM, washed with water and brine, dried, concentrated and purified by silica gel column chromatography using a gradient of 0-25% of ethyl acetate in hexanes to give 92 mg of aldehyde 17. .

Step 2: To 600 mg (1.37 mmol) of aldehyde 17 in 12 mL of acetonitrile was added 533 mg (8.2 mmol) of KCN, 22 mg (0.068 mmol) of ZnI ₂ and 269 mg (1.78 mmol) of TBDSCl. Thereafter, the reaction mixture was stirred at 50 ° C. overnight. The solvent was evaporated and the residue obtained was re-dissolved in EtOAc and washed with water and brine to afford compound 18.

Step 3: Compound 18 (638 mg, 1.1 mmol) was dissolved in 10 mL of DCM, quenched to -78 ° C and treated with 1.78 mL (1.78 mmol) DIBAL. The reaction mixture was allowed to warm to 0 ° C. and stirred at this temperature for 2 hours. 1.5 mL of 1N H ₂ SO ₄ was added and the reaction mixture was stirred at 0 ° C. for another 1 hour. The reaction mixture was washed with water and brine, dried and concentrated to give aldehyde 19.

Step 4: 73 mg (0.532 mmol) of NaH ₂ PO ₄ , 0.118 mL of 2-methyl-2 in a mixture of 155 mg (0.265 mmol) of aldehyde 19 in 4 mL of tert-butanol and 1 mL of water at 0 ° C. Butene and 77 mg (0.85 mmol) of sodium chloride were added. The reaction mixture was stirred at rt for 1.5 h. Saturated NH ₄ Cl (3 ml) and EtOAc (15 ml) were added. The organic layer was washed with brine, dried and concentrated to give carboxylic acid 20.

Step 5: 160 mg (0.267 mmol) of acid 20 were dissolved in 2 mL of THF and treated with 0.53 mL (0.534 mmol) of 1M solution of TBAF in THF. After stirring overnight, the reaction was quenched with water and extracted with EtOAc and DCM. The organic layer was washed with brine, dried and evaporated to afford carboxylic acid 21.

Step 6: 59 mg (0.134 mmol) of [1,4] in a mixture of 65 mg (0.134 mmol) of carboxylic acid 21 and 34 mg (0.20 mmol) of 4-piperidinopiperidine in 2.0 mL of DCM at 0 ° C. '] -Bipiperidine and 0.044 mL (0.402 mmol) of NMM were added. The mixture was stirred at rt for 5 h, quenched with brine and extracted with EtOAc and DCM. The organic layer was washed with brine, dried and concentrated. The product was purified by preparative TLC using 6% MeOH in DCM to afford 33.5 mg of the compound of Example 25 as a diastereomeric mixture.

Example 25 (diastereomer mixture) ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.90 (1.1H, m), 7.82 (1.1H, m), 7.54 (2.1H, m), 7.14 (2.2H, m), 7.04 (2.2H, m), 6.72 (0.9H, m), 5.04-4.80 (1.4H, ser m), 4.72 (0.3H, d), 4.63-4.44 (1.1H, ser m), 4.36 (0.4H, m), 4.26 (0.3H, m), 4.10-3.77 (1.5H, m), 3.59 (0.7H, m), 3.52-3.32 (0.8H, ser m), 3.00 (0.5H, m ), 2.85 (0.5H, m), 2.69-2.34 (6.5H, ser m), 2.1 -0.7 (23.8H, ser m), 0.65-0.22 (3.2H, ser m), 0.12 (0.4H, m) , -0.38 (0.4H, m), -0.50 (0.2H, m). LCMS (ES) single peak, retention time 3.63 min; m / z = 636.2 (M + H) ⁺ .

Example  Preparation of the compound of 26 to 29

The compounds of Examples 26-29 were prepared by a method similar to that used to prepare the compound of Example 25, except that the appropriate amine was used instead of 4-piperidinopiperidine in step 6. That is, for example, the compound of Example 26 was prepared using L-prolinol instead of 4-piperidinopiperidine.

Example  Preparation of compounds of 30 and 31

Methyl ester 22 was prepared in a similar manner to the method of ethyl ester 5 of Example 173 in US Patent Application No. 10 / 358,898 as follows.

Preparation of Methyl Ester 25

Step 1: A solution of 6-bromopicolinic acid (20.0 g, 99 mmol) in DMF (60 mL) was treated with K ₂ CO ₃ (16.6 g, 120 mmol) followed by MeI (6.8 mL, 109 mmol). After 18 h, the reaction mixture was diluted with H ₂ O and extracted with EtOAc (2 ×). The combined organic extracts were washed with H ₂ O (3 ×) and brine, MgSO ₄ Drying above and concentration in vacuo gave bromide 22 (16.9 g, 79%) as an off-white solid.

Step 2: A solution of bromide 22 (16.9 g, 78.2 mmol) in dioxane (120 mL) was added to tributyl (vinyl) tin (25.1 mL, 86 mmol) and Pd (Ph ₃ P) ₂ Cl ₂ (2.0 g, 2.85 mmol). ) And heated to reflux. After 48 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo. The obtained residue was diluted with saturated aqueous NH ₄ Cl and extracted with EtOAc (3 ×). The combined organic extracts were stirred with a solution of KF (20 g) in H ₂ O (300 mL) for 30 minutes, filtered through celite and washed with EtOAc. The filtrate was washed with brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (5 → 15% EtOAc / Hex) gave compound 23 (9.3 g, 73%) as a yellow solid.

Step 3: A solution of compound 23 (22.5 g, 138 mmol) in MeOH (400 mL) and glacial acetic acid (100 mL) was treated with platinum oxide (2.0 g) and stirred under H ₂ (1 atm). After 36 h, the reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue obtained was diluted with saturated sodium carbonate and extracted with CH ₂ Cl ₂ ( ₂ ×). The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo to afford amine 24 (23.5 g,> 99%) as a clear oil.

Step 4: A solution of amine 24 (23.5 g, 137 mmol) in DCE (400 mL) was treated with Et ₃ N (57 mL, 411 mmol) and 4-chlorobenzenesulfonylchloride (34.8 g, 165 mmol) and heated To reflux. After 18 hours, the reaction mixture was cooled to room temperature and washed successively with 1N HCl, 1N NaOH and H ₂ O, dried over MgSO ₄ and concentrated in vacuo. Recrystallization from EtOAc / Hex (1: 4) gave compound 25 (26.5 g). The filtrate was concentrated and recrystallized as above to give a second batch (5.0 g), and the filtrate was further recrystallized as above to give a third batch (4.2 g, 75% total yield) as a white solid. ) Was obtained.

Scheme 4

Step 1: A solution of ester 25 (10.0 g, 28.9 mmol) and N, O-dimethylhydroxylamine hydrochloride (4.24 g, 43.5 mmol) in THF (290 mL) at −20 ° C. was converted to i-PrMgCl (43.5 mL, 87 mmol; 2.0 M in THF) dropwise. The reaction mixture was allowed to warm to ambient temperature over 2 hours. After an additional 2 hours, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (2 ×). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo to give amide 26 (10.8 g,> 99%) as a clear oil.

Step 2: A solution of crude amide 26 (10.8 g) in THF (260 mL) at 0 ° C was treated with MeMgBr (19.3 mL, 58 mmol; 3.0 M in Et ₂ O). After 2 hours, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with Et ₂ O (2 ×). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. Polishing at 5 ° C. (5% EtOAc / Hex) gave ketone 27 (5.99 g). The filtrate was concentrated and triturated as above to give an additional 0.7 g (70% total yield) of ketone 27 as a white solid.

Step 3: A solution of ketone 27 (4.1 g, 12.43 mmol) in THF (80 mL) at −78 ° C. was treated with LDA (6.84 mL, 13.67 mmol; 2.0 M in heptane / THF / ethylbenzene). After 30 minutes, a solution of 2- [N, N-bis (trifluoromethylsulfonyl) amino] -5-chloropyridine (6.35 g, 16.16 mmol) in THF (20 mL) was added dropwise. After 4 hours, the reaction mixture was warmed to 0 ° C. After an additional 30 minutes, the reaction mixture was diluted with saturated aqueous NaHCO ₃ and extracted with Et ₂ O (2 ×). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford crude 28. Solid residue was added to a solution of CH ₃ CN [purged with CO (g) for 45 min]. The solution was treated with n-Bu ₃ N (5.92 mL, 24.86 mmol), MeOH (60 mL), LiCl (0.53 g, 12.43 mmol) and (Ph ₃ P) ₄ Pd (1.40 g, 1.25 mmol). The reaction mixture was evacuated to contact with CO (1 atm) and heated to reflux under 1 atm CO. After 24 hours, the reaction mixture was cooled to ambient temperature and concentrated to remove MeOH. The residue was diluted with Et ₂ O and 1N HCl and extracted with Et ₂ O (2 ×). The combined organic layers were washed with 1N HCl, saturated aqueous NaHCO ₃ , and brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (3 → 10% EtOAc / Hex) to ketone 27 (Rf = 0.63, unreacted) as ester 29 (Rf = 0.53, 10% EtOAc / Hex, 2.05 g, 44% over two steps) as a clear oil. 10% EtOAc / Hex, 930 mg).

Step 4: A solution of ester 29 (2.38 g, 6.40 mmol) in THF (60 mL) at −78 ° C. was treated with DIBAL (25 mL, 25 mmol; 1.0 M in Hex) and warmed to ambient temperature over 30 minutes. After an additional 2 hours, the reaction mixture was quenched with 1N HCl and extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (20% EtOAc / Hex) gave olefin 30 (2.03 g, 92%) as a clear oil.

Step 5: A solution of Et ₂ Zn (29 mL, 29 mmol; 1.0 M in Hex) in DCE (50 mL) was added dropwise over 20 minutes with dichloroiodomethane (2.10 mL, 29 mmol) at -20 ° C. . After a further 5 minutes, a solution of olefin 30 (2.0 g, 5.90 mmol) in DCE (30 mL) was added dropwise and the reaction mixture was allowed to warm at ambient temperature over 30 minutes. After an additional 2.5 hours, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ ( ₂ ×). The combined organic layers were washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo to afford alcohol 31 (1.98 g, 94%) as a white solid.

Step 6: A solution of alcohol 31 (650 mg, 1.82 mmol) in CH ₃ CN / ToI (30 mL, 1: 2) at 0 ° C. was added Ph ₃ P (630 mg, 2.40 mmol), imidazole (375 mg, 5.5 mmol), and I ₂ (609 mg, 2.40 mmol). After 1.5 h, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with Et ₂ O. The combined organic layers were washed with saturated aqueous NaHCO ₃ , and brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (5% EtOAc / Hex) gave iodide 32 (600 mg, 70%) as a white solid.

Step 7: A solution of iodide 32 (2.73 g, 5.84 mmol) in CH ₃ CN (60 mL) was treated with n-Bu ₄ NCN (1.90 g, 7.0 mmol). After 1.5 h, the reaction mixture was diluted with H ₂ O and extracted with EtOAc (2 ×). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (10% EtOAc / Hex) gave nitrile 33 (1.85 g, 86%) as a white solid.

Step 8: A solution of nitrile 33 (1.38 g, 3.76 mmol) in CH ₂ Cl ₂ (40 mL) at −78 ° C. was treated with DIBAL (5.6 mL, 5.6 mmol; 1.0 M in Hex) and 2 h at −10 ° C. Warmed over. After an additional hour, the reaction mixture was quenched with 1N HCl and 2 mL MeOH and stirred vigorously. After 30 minutes, the biphase solution was extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo to afford crude Compound 34 (1.4 g). Crude residue was dissolved in a solution of t-BuOH / H ₂ O (4: 1, 40 mL) cooled to 0 ° C., cooled to 0 ° C., NaH ₂ PO ₄ (1.04 g, 7.52 mmol), 2-methyl Treated with ₂ -butene (9.4 mL, 18.8 mmol; 2.0 M in THF) and NaClO ₂ (1.09 g, 12.0 mmol) and warmed to ambient temperature. After 45 minutes, the reaction mixture was diluted with saturated aqueous NH ₄ Cl and extracted with EtOAc (3 ×). The combined organic layers were washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo to afford acid 35 (1.56 g,> 99%) as a white solid.

Step 9: A solution of acid 35 (30 mg, 0.078 mmol) in CH ₂ Cl ₂ (1 mL) was treated with oxalyl chloride (60 μL, 0.70 mmol). After 30 minutes, the reaction mixture was concentrated in vacuo, diluted with CH ₂ Cl ₂ (1 mL) and Et ₃ N (98 μL, 0.70 mmol) followed by 4-piperidinopiperidine (27 mg, 0.16 mmol) Treated with. After 3 h, the reaction mixture was purified directly via preparative TLC (5% MeOH / CH ₂ Cl ₂ ) to afford the compound of Example 30 (25 mg, 60%) as a yellow oil.

Example 30: ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.77 (dd, J = 8.1, 4.4 Hz, 2H), 7.46 (dd, J = 8.8, 5.9 Hz, 2H), 4.75-4.54 (m , 2 H), 3.92 (m, l H), 3.73 (m, 1H), 3.40 (d, J = 16.2 Hz, 1H), 2.99 (m, 1H), 2.59-2.43 (m, 7H), 1.94 -1.67 (m, 6H), 1.58-1.43 (m, 5H), 1.22-1.02 (m, 6H), 0.97 (t, J = 7.3 Hz, 3H), 0.90-0.50 (m, 5H ). LCMS (ES) retention time 3.62 min, m / z 536.1 (M + H ⁺ ).

Step 9a: A solution of acid 35 (40 mg, 0.104 mmol) in CH ₂ Cl ₂ (2 mL) was extracted with piperidine (15 μL, 0.156 mmol), Et ₃ N (31 μL, 0.22 mmol) and BOP reagent (60 mg, 0.135 mmol). After 18 h, the reaction mixture was directly purified via preparative TLC (25% EtOAc / Hex) to afford the compound of Example 31.

Compound of Example 31: as a yellow solid (35.3 mg, 75%). LCMS (ES) retention time 4.38 min, m / z 453.1 (M + H ⁺ ).

Example  Preparation of the compound of 32 to 33

The compounds of Examples 32-33 below were prepared by reacting acid 35 with an appropriate cyclic amine (ie, rather than 2-piperidinopiperidine) under conditions similar to those described in step 9 above. That is, for example, the compound of Example 33 was prepared by reacting acid 35 with (+/-)-1,4-diazabicyclo [4.4.0] decane instead of 2-piperidinopiperidine.

Example  Preparation of the compound of 34 to 38

The compounds of Examples 34 to 38 below were prepared by reacting acid 35 with an appropriate cyclic amine (rather than using piperidine) under conditions similar to those described in step 9a above. That is, for example, the compound of Example 34 was prepared by reacting acid 35 with (R)-(+)-3-pyrrolidinol instead of piperidine.

Example  Preparation of Compounds 39 to 40

Olefin 36 was prepared by the method provided for Example 1 in US Pat. No. 0229902.

Scheme 5

Step 1: A solution of Et ₂ Zn (48.4 mL, 48.4 mmol; 1.0 M in Hex) in CH ₂ Cl ₂ (20 mL) at 0 ° C. was treated with TFA (3.7 mL, 48.4 mmol). After 5 minutes, CH ₂ I ₂ (3.9 mL, 48.4 mmol) was added. After a further 5 minutes, a solution of olefin 36 (5.2 g, 12.1 mmol) in CH ₂ Cl ₂ (40 mL) was added and the reaction mixture was slowly warmed to ambient temperature. After 2 h, the reaction mixture was quenched with MeOH, diluted with H ₂ O and extracted with CH ₂ Cl ₂ (4 ×) followed by EtOAc (2 ×). The combined organic layers were washed, dried over MgSO ₄ and concentrated in vacuo to yield silyl ether 37 (6.1 g,> 99%) as a clear oil.

Step 2: A solution of silyl ether 37 (25 g, 56.3 mmol) in THF (250 mL) at 0 ° C. was treated with TBAF (110 mL, 110 mmol; 1.0 M in THF) and warmed to ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo, diluted with 1N HCl and Et ₂ O and extracted with Et ₂ O (3 ×). The combined organic layers were washed with 1N HCl (2 ×), H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (0 → 5% MeOH / CH ₂ Cl ₂ ) afforded crude alcohol 38 (26.2 g) as a white solid.

Step 3: Treatment of crude alcohol 38 (26.2 g) in CH ₂ Cl ₂ (500 mL) at 0 ° C. with pyridine (8.7 mL, 101 mmol) followed by death-martin periodinan (34 g, 80 mmol) And warmed to ambient temperature. After 2.5 hours, H ₂ O (3 drops) was added. After an additional 30 minutes, the reaction mixture was concentrated in vacuo, diluted with Et ₂ O and washed with saturated aqueous NaHCO ₃ / ZNa ₂ S ₂ O ₃ (1: 1). The aqueous layer was back-extracted with Et ₂ O (2 ×). The combined organic layers were washed with 1N HCl (2 ×), saturated aqueous NaHCO ₃ , and brine, dried over MgSO ₄ and concentrated in vacuo. Polishing at 0 ° C. (2: 3: 25 EtOAc / Et ₂ O / Hex) gave crude aldehyde 39 (20.3 g) as a white solid.

Step 4: A solution of aldehyde 39 (20.3 g) in THF (500 mL) at 0 ° C. was treated with MeMgBr (28 mL, 84 mmol; 3.0 M in Et ₂ O) and warmed to ambient temperature over 1 h. After an additional 15 minutes, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and concentrated in vacuo. The aqueous solution was extracted with Et ₂ O ( ₂ ×). The combined organic layers were washed with saturated aqueous NaHCO ₃ , and brine, dried over MgSO ₄ and concentrated in vacuo to afford 40 (17.8 g, 92% over 3 steps) as a white solid.

Step 5: A solution of alcohol 40 (17.8 g, 51.8 mmol) in CH ₂ Cl ₂ (500 mL) at 0 ° C. was followed by pyridine (6.6 mL, 77 mmol) followed by des-martin periodinan (28.8 g, 68 mmol) And warmed to ambient temperature. After 4 hours, the reaction mixture was concentrated in vacuo, diluted with Et ₂ O and washed with saturated aqueous NaHCO ₃ / Na ₂ S ₂ O ₃ (1: 1). The aqueous layer was back-extracted with Et ₂ O (2 ×). The combined organic layers were washed with 1N HCl (2 ×), saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and concentrated in vacuo. Polishing at 10 ° C. (10% EtOAc / Hex) gave ketone 41 (13.5 g). The filtrate was concentrated and triturated as above to give compound 41 as a white solid as a second product (2.1 g, total yield 88%).

Step 6: A solution of ketone 41 (2.56 g, 7.50 mmol) in THF (50 mL) was treated with LDA (4.1 mL, 8.25 mmol; 2.0 M in heptane / THF / ethylbenzene) at -78 ° C. After 30 minutes, a solution of 2- [N, N-bis (trifluoromethylsulfonyl) amino] -5-chloropyridine (3.8 g, 9.68 mmol) in THF (10 mL) was added dropwise. After 4 hours, the reaction mixture was warmed to 0 ° C. After an additional 2.5 hours, the reaction mixture was diluted with saturated aqueous NaHCO ₃ and extracted with Et ₂ O (2 ×). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford crude product 42. The solid residue was added to a solution of CH ₃ CN [purged with CO (g) for 30 minutes]. The solution was diluted with n-Bu ₃ N (3.57 mL, 15 mmol), MeOH (25 mL), LiCl (0.32 g, 7.5 mmol) and Ph ₃ P (0.39 g, 1.5 mmol) and Pd (dba) ₂ (0.43 g). , 0.75 mmol). The reaction mixture was evacuated and contacted with CO (1 atm) and heated to reflux under 1 atm CO. After 12 hours, the reaction mixture was cooled to ambient temperature and concentrated to remove MeOH. The residue was diluted with Et ₂ O and 1N HCl and extracted with Et ₂ O (3 ×). The combined organic layers were washed with 1N HCl, saturated aqueous NaHCO ₃ , and brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (3 → 10% EtOAc / Hex) gave ester 43 (Rf = 0.53, 10% EtOAc / Hex, 790 mg, 27% over 2 steps) as unreacted ketone 41 (Rf = 0.63, 10% EtOAc / Hex, 730 mg).

Step 7: A solution of ester 43 (1.79 g, 4.66 mmol) in THF (50 mL) at −78 ° C. was treated with DIBAL (14 mL, 14 mmol; 1.0 M in Hex) and warmed to ambient temperature over 30 minutes. After an additional hour, the reaction mixture was cooled to 0 ° C., quenched with 1N HCl and extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (20% EtOAc / Hex) gave olefin 44 (1.5 g, 90%) as a clear oil.

Step 8: A solution of Et ₂ Zn (17 mL, 17 mmol; 1.0 M in Hex) in DCE (30 mL) was added dropwise over 20 minutes with chloroiodomethane (1.24 mL, 17 mmol) at -20 ° C. . After a further 5 minutes, a solution of olefin 44 (1.5 g, 4.21 mmol) in DCE (20 mL) was added dropwise and the reaction mixture was allowed to warm to ambient temperature over 30 minutes. After an additional 2.5 hours, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ ( ₂ ×). The combined organic layers were washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo to afford 45 (1.57 g,> 99%) of alcohol as a clear oil.

Step 9: A solution of alcohol 45 (1.5 g, 4.21 mmol) in CH ₃ CN / ToI (40 mL, 1: 2) at 0 ° C. was added with Ph ₃ P (1.3 g, 5.0 mmol), imidazole (0.82 g, 12.0). mmol) and I ₂ (1.27 g, 5.0 mmol). After 20 minutes, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with Et ₂ O (2 ×). The combined organic layers were washed with saturated aqueous NaHCO ₃ , and brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (3% EtOAc / Hex) gave iodide 46 (1.6 g, 79%) as a clear oil.

Step 10: A solution of iodide 46 (1.6 g, 3.33 mmol) in CH ₃ CN (40 mL) was treated with n-Bu ₄ NCN (1.4 g, 5.1 mmol). After 2 h, the reaction mixture was diluted with saturated aqueous NH ₄ Cl and extracted with Et ₂ O (3 ×). The combined organic layers were washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. Flash chromatography (10% EtOAc / Hex) gave nitrile 47 (1.0 g, 79%) as a white solid.

Step 11: Treat a solution of nitrile 47 (1.O g, 2.64 mmol) in CH ₂ Cl ₂ (30 mL) at −78 ° C. with DIBAL (4.7 mL, 4.7 mmol; 1.0 M in Hex) and return to 0 ° C. 1 Warmed over time. After an additional 15 minutes, the reaction mixture was quenched with 1N HCl and 2 mL MeOH and stirred vigorously. After 30 minutes, the biphasic solution was extracted with CH ₂ Cl ₂ (3 ×). The combined organic layers were washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo to afford crude Compound 48 (950 mg). The crude residue was dissolved in a solution of t-BuOH / H ₂ O (4: 1, 30 mL) cooled to 0 ° C., cooled to 0 ° C., NaH ₂ PO ₄ (730 mg, 5.28 mmol), 2-methyl-2 Treated with butene (6.6 mL, 13.2 mmol; 2.0 M in THF) and NaClO ₂ (764 mg, 8.45 mmol) and warmed to ambient temperature. After 1.5 h, the reaction mixture was diluted with saturated aqueous NH ₄ Cl and extracted with EtOAc (3 ×). The combined organic layers were washed with H ₂ O, dried over MgSO ₄ and concentrated in vacuo to give acid 49 (1.03 g, 98%) as a white solid.

Step 12: Treat a solution of acid 49 (50 mg, 0.125 mmol) in CH ₂ Cl ₂ (2 mL) at 0 ° C. with i-Pr ₂ NEt (110 μL, 0.625 mmol) and HATU (61 mg, 0.163 mmol) It was. After 10 minutes a dihydrochloride salt of 2-methyl-2-piperazin-1-yl-propan-1-ol (43 mg, 0.188 mmol, see WO 2001007441) was added. After 18 h, the reaction mixture was diluted with saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ ( ₂ ×). The combined organic layers were washed with saturated aqueous NaHCO ₃ , MgSO ₄ Dry over and concentrate in vacuo. Preparation TLC (0.5: 4.5: 95 NH ₄ OH / MeOH / CH ₂ Cl ₂ ) afforded the compound of Example 39 as a yellow solid, which was dissolved in Et ₂ O (2 mL) and HCl (1.0 mL, Et ₂ O). 1N) and then polished to give the hydrochloride salt (23.4 mg, 32%) as a yellow solid.

Example 39: ¹ H NMR (free base) (CDCl ₃ , 400 MHz) δ 7.71 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 4.54 (d, J = 6.6 Hz , 1H), 3.67-3.55 (m, 4H), 3.42-3.34 (m, 2H), 2.97 (m, 1H), 2.82-2.52 (m, 6H), 1.95 (m, 1H), 1.66 (m, 1H ), 1.56-1.43 (m, 2H), 1.21-0.90 (m, 7H), 0.86 (m, 1H), 0.75-0.52 (m, 6H), 0.23 (m, 1H). LCMS (ES): retention time 3.31 min, m / z 538.3 (M + H ⁺ ).

Step 12a: A solution of acid 49 (50 mg, 0.125 mmol) in CH ₂ Cl ₂ (2 mL) was treated with oxalyl chloride (100 μL, 1.16 mmol). After 20 minutes, the reaction mixture was concentrated in vacuo, diluted with CH ₂ Cl ₂ (1 mL) and Et ₃ N (130 μL, 1.20 mmol) followed by (+/-)-1,4-diazabicyclo [4.4 .0] decane (140 mg, 1.0 mmol). After 18 h, the reaction mixture was diluted with saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ ( ₂ ×). The combined organic layers were washed with saturated aqueous NaHCO ₃ , dried over MgSO ₄ and concentrated in vacuo. Preparation TLC (0.5: 4.5: 95 NH ₄ OH / MeOH / CH ₂ Cl ₂ ) afforded the compound of Example 40 (42.0 mg, 65%) as a yellow oil.

Example 40: LCMS (ES): retention time 3.45 minutes, m / z 520.3 (M + H ⁺ ).

Example  Preparation of Compounds 41 and 42

The compounds of Examples 40 and 41 below are prepared by reacting acid 49 with an appropriate cyclic amine (ie, 2-methyl-2-piperazin-1-yl-propan-1-ol) under similar conditions as described in step 12 above. Rather than used). That is, for example, the compound of Example 41 can be prepared by replacing the acid 49 with 2-((2S) -2-methyl-piperazin-1- Prepared by reaction with I) -ethanol.

Example  Preparation of Compounds 43 and 44

The compounds of Examples 43 to 44 below are prepared by the appropriate cyclic amines (ie, Rather than using). That is, for example, the compound of Example 44 reacts acid 49 with octahydro-pyrrolo [1,2-a] pyrazine instead of (+/-)-1,4-diazabicyclo [4.4.0] decane It was prepared by.

Example  Preparation of 45 Compounds

Example  45

Scheme 6

Step 1 : Cyclopropanecarboxaldehyde 50 is described in J. Am. Chem. Soc. 1992, 114 (24), 9369-86 (Andrew G. Myers, Dragovich S. Peter, and Kuo Y. Elaine). A solution of this aldehyde (10.0 g, 28.4 mmol) in toluene (60 mL) was treated with 1-triphenylphosphoranylidene-2-propanone (22.0 g, 63.0 mmol) and the reaction mixture was heated at reflux for 16 h. It was. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by chromatography on silica gel (eluted with hexanes / EtOAc 8: 2) to afford 6.0 g of ketone 51.

Step 2 : KHMDS (17.0 mmol, 17.0 mL, 1.0 M in THF) was slowly added to a solution of ketone 51 prepared in step 1 (6.0 g, 15.3 mmol) in THF (20 mL) at -78 ° C. The reaction mixture was stirred at −30 ° C. for 1 hour, cooled to −78 ° C. and treated with a solution of TBSCl (3.0 g, 17.0 mmol) in THF (20 mL). The mixture was stirred at −78 ° C. for 2 hours and allowed to warm to room temperature over 16 hours. After quenching with saturated aqueous NH ₄ Cl, the mixture was extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated to yield 7.74 g of diene 52.

Step 3 : Diene 52 prepared in Step 2 (7.6 g, 15.0 mmol), p-chlorobenzenesulfonamide (1.44 g, 7.5 mmol), cyclopropanecarboxaldehyde (0.75 g, 10.5 mmol) and THF (5 mL) The mixture was heated at reflux for 12 h. Cool to room temperature, remove solvent and obtain a mixture of cis and trans product (cis / trans = 2; 1), which is separated by flash chromatography (eluted with hexanes / EtOAc 8: 2) to yield 1.50 g of the desired product. Cis sulfonamide 53 was obtained as a solid.

Step 4 : Concentrated HCl (0.75 mL) was slowly added to a solution of sulfonamide 53 (1.5 g, 2.0 mmol) prepared in step 3 in DCM (15 mL) at 0 ° C. After stirring at 0 ° C. for 2 hours, the mixture was neutralized with saturated aqueous NaHCO ₃ , the layers separated, and the organic phase was dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography on silica gel (eluted with hexanes / EtOAc 9: 1) to give 1.2 g ketone 54 as a white solid.

Step 5 : To a solution of ketone 54 (0.97 g, 1.5 mmol) prepared in step 4 in THF (10 mL) was added CeCl ₃ .7H ₂ O (0.12 g) followed by NaBH ₄ (0.61 g, mmol). The cooling bath was removed and the reaction mixture was stirred at rt for 1 h. The mixture was diluted with water, extracted with EtOAc, dried over Na ₂ S0 ₄ and concentrated. The residue was purified by chromatography on silica gel (eluted with hexanes / EtOAc 7: 3) to yield 0.69 g of alcohol 55 as a clear oil.

Step 6 : A solution of alcohol 55 (0.691 g, 1.1 mmol), acetic anhydride (10.8 g, .106 mmol) and p-toluenesulfonic acid monohydrate (60 mg, 0.32 mmol) prepared in step 5 was used for 16 hours at room temperature. Was stirred. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO ₄ and concentrated to give 0.67 g of compound 56 as a clear oil.

Step 7 : A solution of compound 56 (610 g, 0.9 mmol) prepared in step 6 in THF (40 mL) was treated with TBAF (1.3 ml, 1.3 mmol, 1M in THF). The reaction mixture was stirred at rt for 1 h. After the solvent was removed in vacuo, the crude mixture was extracted with EtOAc. The organic phase was washed with water followed by saturated aqueous NaHCO ₃ and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the crude product was purified by flash chromatography (eluted with hexanes / EtOAc 7/3) to afford 0.386 g of alcohol 57 as a clear oil.

Step 8 : 4-acetamido- in a rapidly stirred solution of alcohol 57 (386 mg, 0.87 mmol) prepared in step 7 in CH ₂ Cl ₂ (2 mL) and H ₂ O (0.5 mL) at 0 ° C. TEMPO (1.8 mg, 0.01 mmol), [CH ₃ (CH ₂ ) ₃ ] ₄ N ⁺ HSO ₄ ⁺ (77 mg, 0.23 mmol) and NaBr (9 mg, 0.09 mmol) were added successively. Thereafter, aqueous NaOCl (0.83 M, 2.1 mL, 1.74 mmol) containing NaHCO ₃ (250 mg) was added and the mixture was vigorously stirred for 20 minutes. The organic solvent was evaporated under reduced pressure and the residue was combined with aqueous citric acid (10%, 10 mL) containing EtOAc (20 mL) and Kl (60 mg). The aqueous phase was reextracted with EtOAc and the combined organic phases were washed with aqueous Na ₂ S ₂ O ₃ and brine and dried (MgSO ₄ ). The organic phase was evaporated under reduced pressure to give 396 mg of acid 58 as a yellow solid.

Step 9 : To a solution of the acid 58 (395 mg, 0.87 mmol) prepared in step 8 in MeOH (15 mL) was added K ₂ CO ₃ (723 mg, 5.23 mmol). The mixture was stirred at rt for 1 h and the solvent was removed under reduced pressure. The residue was taken up in water, acidified with 1N HCl and extracted with EtOAc. The organic phase was dried (MgSO ₄ ) and concentrated under reduced pressure to give 293 mg of acid 59.

Step 10 : To a mixture of acid 50 (50 mg, 0.12 mmol) prepared in step 9 in 2.0 mL of DMF was added iPr ₂ NEt (62 mg, 0.48 mmol) and HATU (60 mg, 0,16 mmol). After stirring for 5 minutes, 2-methyl-2-piperazin-1-yl-propan-1-ol (43 mg, 0.18 mmol as dihydrochloride salt) was added and the mixture was stirred at rt for 16 h. The mixture was diluted with EtOAc, washed with water and brine and dried (Na ₂ SO ₄ ). The organic phase was loaded onto a prepared TLC plate (silica gel) using 5% MeOH in DCM as solvent to give 33 mg of the compound of Example 45.

Example 45: ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.0 Hz), 4.20 (1H, t, J = 8.0 Hz) , 3.75-3.40 (4H, m), 3.38-3.28 (3H, m), 3.10-3.0 (1H, m), 2.88-2.78 (1H, m), 2.72-2.45 (4H, m), 1.97-1.75 ( 4H, m), 1.47-1.35 (1H, m), 1.25-1.10 (3H, m), 1.03 (6H, s), 0.90-0.47 (7H, m), 0.33-0.22 (1H, m). LCMS (ES) retention time 2.60 min, m / z 554.1 (M + H) ⁺ .

Example  Preparation of Compounds 46-49

The compounds of Examples 46 to 49 below give acid 59 rather than a suitable cyclic amine (ie, 2-methyl-2-piperazin-1-yl-propan-1-ol) under conditions similar to those described in step 10 above. Prepared by reaction with That is, for example, the compound of Example 46 was prepared by reacting acid 49 with 4-piperidinopiperidine instead of 2-methyl-2-piperazin-1-yl-propan-1-ol.

black

Gamma secretase activity is described in its entirety herein by Zhang et al. (Biochemistry, 40 (16), 5049-5055, 2001). Activity is expressed as the concentration of compound that inhibits 50% of the enzyme activity or as a percentage inhibition.

reagent

Antibodies W02, G2-10, and G2-11 were obtained from Dr. Konrad Beyreuther (Heidelberg University, Heidelberg, Germany). W02 recognizes residues 5-8 of the Aβ peptide, while G2-10 and G2-11 recognize the specific C-terminal structures of Aβ 40 and Aβ 42, respectively. Biotin-4G8 was obtained from Senenetec (St. Louis, MO). All tissue culture reagents used in this operation were obtained from Life Technologies, Inc. unless otherwise indicated. Pepstatin A is from Roche Molecular Biochemicals; DFK167 was obtained from Enzyme Systems Products (Livermore, Calif.).

cDNA construction, tissue culture and cell line construction

Construct SPC99-Lon, containing the first 18 residues and the C-terminal 99 amino acids of APP with a London mutation, is described (Zhang, L., Song, L., and Parker, E. (1999) J. Biol. Chem. 274, 8966-8972. Upon insertion into the membrane, 17 amino acid signal peptides are processed, leaving additional leucine at the N-terminus of Aβ. SPC99-lon was cloned into pcDNA4 / TO vector (Invitrogen) and transfected into 293 cells stably transfected with pcDNA6 / TR provided in the T-REx system (Invitrogen). . The transfected cells were Dulbecco modified with 10% fetal bovine serum, 100 units / mL penicillin, 100 g / mL streptomycin, 250 g / mL zeosin, and 5 g / mL blastinikidine (Invitrogen). Selection was made in Dulbecco's modified Eagle's media (DMEM). Colonies were cloned for Aβ production by inducing C99 expression for 16-20 hours using 0.1 g / mL tetracycline and analyzing the conditioned medium using a sandwich immunoassay (see below). One of the clones designated pTRE.15 was used in this study.

Intracellular C99 expression was induced for 20 hours using 0.1 g / mL tetracycline. Cells were pretreated with 1M phorbol 12-myristate 13-acetate (PMA) and 1M brefeldin A (BFA) at 37 ° C. for 5-6 hours before harvesting. Cells were washed three times with cold phosphate-buffered saline (PBS) and purified with 20 mM Hepes (pH 7.5), 250 mM sucrose, 50 mM KCl, 2 mM EDTA, 2 mM EGTA, and complete protease inhibitor tablets [Roche Harvested in Buffer A containing Roche Molecular Biochemicals. Cell pellets were flash-frozen in liquid nitrogen and stored at −70 ° C. prior to use.

To prepare the membrane, cells were resuspended in Buffer A and digested at 600 psi in a nitrogen bomb. Cell lysates were centrifuged at 1500 g for 10 minutes to remove nuclei and large amounts of cell debris. The supernatant was centrifuged at 100000 g for 1 hour. Membrane pellets were resuspended in Buffer A and 0.5 M NaCl and the membrane was collected by centrifugation at 200000 g for 1 hour. Salt-washed membrane pellets were again washed in Buffer A and centrifuged at 100000 g for 1 hour. The final membrane pellet was resuspended in a small volume of buffer A using a Teflon-glass homogenizer. Protein concentration was measured and membrane aliquots were flash-frozen in liquid nitrogen and stored at -70 ° C.

γ-secretase response and Aβ analysis

To measure γ-secretase activity, the membranes were incubated at 37 ° C. for 1 hour in 50 L of buffer containing 20 mM Hepes (pH 7.0) and 2 mM EDTA. At the end of incubation, Aβ 40 and Aβ 42 were measured using an immunoassay based on electrochemiluminescence (ECL). Aβ 40 was identified as antibody pair TAG-G2-10 and Biotin-W02, while Aβ 42 was identified as TAG-G2-11 and Biotin-4G8. ECL signals were measured according to the manufacturer's instructions using an ECL-M8 device (now International, Inc.). Data shown were the average of two or three measurements of each test. The characteristics of the described γ-setletase activity were confirmed using at least 5 separate membrane formulations.

When using this assay, the compounds of Examples 1-49 exhibited IC ₅₀ values in the range of about 0.001 to about 0.5 μM. The compounds of Examples 1-11, 17 and 19-48 exhibit IC ₅₀ values in the range of about 0.001 to about 0.2 μM. The compounds of Examples 1-5, 19-25, 28-30, 32, 33, 36-40, 42, 45, 46, and 48 exhibited IC ₅₀ values in the range of about 0.001 to about 0.02 μΜ.

The γ-secretase inhibitory activity of some compounds of the invention is shown below:

Although the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and variations thereof will be apparent to those skilled in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the invention.

Claims (49)

Compounds of Formula (I), or pharmaceutically acceptable salts, solvates and / or esters thereof: Formula I

Where R ¹ is selected from the group consisting of unsubstituted aryl, aryl substituted by one or more R ⁵ groups, unsubstituted heteroaryl, and heteroaryl substituted by one or more R ⁵ groups; R ² is —C (O) —Y, —alkylene-C (O) —Y, —alkylene-cycloalkylene-C (O) —Y, —cycloalkylene-alkylene-C (O) — Y, -alkylene-cycloalkylene-alkylene-C (O) -Y, -cycloalkylene-C (O) -Y, -S (O) -Y, -alkylene-S (O) -Y , -Alkylene-cycloalkylene-S (O) -Y, -cycloalkylene-alkylene-S (O) -Y, -alkylene-cycloalkylene-alkylene-S (O) -Y,- Cycloalkylene-S (O) -Y, -S (O ₂ ) -Y, -alkylene-S (O ₂ ) -Y, -alkylene-cycloalkylene-S (0 ₂ ) -Y, -cyclo an alkylene-alkylene -S (O ₂₎ -Y, - alkylene-cycloalkylene-alkylene -S (O ₂₎ -Y, and - cycloalkylene -S (O ₂₎ from the group consisting of -Y Selected; Wherein each of said alkylene or cycloalkylene is unsubstituted or optionally substituted by one or more hydroxy groups, provided no hydroxy group is bonded to a carbon atom, wherein the carbon atom is also bonded to a sulfur atom. No; (R ³⁾ ₂ each of R ³ is H, alkyl, -O- ^{alkyl, -OH, -N (R 9)} 2, acyl and independently selected from the group consisting of days aroyl; or Residue (R ³ ) ₂ , together with the ring carbon atom shown as bound in formula (I), defines a carbonyl group, -C (O)-, provided that when m is an integer greater than 1, at most one carbonyl The group is present in the ring shown in formula (I); Each R ^3A And R ^3B is independently selected from the group consisting of H and alkyl; R ⁵ is halo, -CF ₃ . -OH, alkoxy, -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl, -OC (O) -alkyl, -C (O) O-aryl, -OC (O) -aryl, -C (O) NR ⁶ R ⁷ , -alkylene-NR ⁶ R ⁷ , -N (R ⁶ ) C (O) -alkyl, -N (R ⁶ ) C (O) -aryl, -N (R ⁶ ) C (O) -heteroaryl and -N (R ⁶ ) C (O) NR ⁶ R ⁷ are independently selected from the group consisting of; Y is —NR ⁶ R ⁷ , —N (R ¹² ) (CH ₂ ) _b NR ⁶ R ⁷ , wherein b is an integer from 2 to 6, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, Arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, aryl alkyl heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted arylcycloalkyl, substituted hetero Arylalkyl, substituted heteroarylcycloalkyl, substituted arylheterocycloalkyl, and substituted heterocycloalkyl alkyl; Wherein said substituted aryl, substituted heteroaryl, substituted arylalkyl, substituted arylcycloalkyl, substituted heteroarylalkyl, substituted heteroarylcycloalkyl, substituted arylheterocycloalkyl, or substituted heterocyclo of the Y group The aryl or heteroaryl moiety in the alkyl alkyl group is halo, -CF ₃ , -OH, alkoxy, -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl, -OC (O) -alkyl,- C (O) O-aryl, -OC (O) -aryl, -C (O) NR ⁶ R ⁷ , -alkylene-NR ⁶ R ⁷ , -N (R ⁶ ) C (O) -alkyl, -N One independently selected from the group consisting of (R ⁶ ) C (O) -aryl, -N (R ⁶ ) C (O) -heteroaryl, -N (R ⁶ ) C (O) NR ⁶ R ⁷ , and alkyl Substituted with one or more substituents; or Y is

Is selected from the group consisting of; R ⁶ and R ⁷ are H, alkyl, alkyl substituted with 1 to 4 hydroxy groups, cycloalkyl, arylalkyl, heteroarylalkyl,

And independently selected from the group consisting of heterocycloalkyl, provided that when R ⁶ and / or R ⁷ is alkyl substituted with 1 to 4 hydroxy groups, none of the hydroxy groups are carbon [wherein Carbon is also bonded to nitrogen; R ⁸ is independently selected from the group consisting of H, —OH, alkyl, —O-alkyl, alkyl substituted with 1 to 4 hydroxy groups, and —C (O) O-alkyl; Or when r is at least 1 and at least two R ⁸ groups are selected from the group consisting of alkyl, -O-alkyl, alkyl substituted with 1 to 4 hydroxy groups, and -C (O) O-alkyl, R ⁸ groups together with the ring carbon atom or ring carbon atom to which they are attached define a ring; Each R ⁹ is H, alkyl, alkyl substituted by 1 to 4 hydroxy groups, cycloalkyl, cycloalkyl substituted by 1 to 4 hydroxy groups, arylalkyl, heteroarylalkyl, -C (O) O -alkyl, -alkyl-alkylene -O- alkylene -OH, at least one R ⁵ group, an aryl substituted aryl, heteroaryl substituted with one or more R ⁵ groups, unsubstituted heteroaryl, unsubstituted, - alkylene- Independently selected from the group consisting of C (O) O-alkyl,-(SO ₂ ) -alkyl,-(SO ₂ ) -aryl, and hydroxyalkyl-O-alkyl; Provided that when R ⁹ is alkyl substituted with 1 to 4 hydroxy groups, none of the hydroxy groups are bonded to carbon, wherein the carbon is also bonded to nitrogen; Each R ¹⁰ is independently selected from the group consisting of H and alkyl; R ¹¹ is aryl, substituted aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, aryl cycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, alkoxyalkyl, substituted heteroaryl, substituted arylalkyl , Substituted arylcycloalkyl, substituted heteroarylalkyl, and substituted arylheterocycloalkyl; Wherein the aryl or heteroaryl moiety in the substituted heteroaryl, substituted arylalkyl, substituted arylcycloalkyl, substituted heteroarylalkyl, and substituted arylheterocycloalkyl of the R ¹¹ group is halo, -CF ₃ ,- OH, alkoxy, -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl, -OC (O) -alkyl, -C (O) O-aryl, -OC (O) -aryl,- C (O) NR ⁶ R ⁷ , -alkylene-NR ⁶ R ⁷ , -N (R ⁶ ) C (O) -alkyl, -N (R ⁶ ) C (O) -aryl, -N (R ⁶ ) Substituted with one or more substituents independently selected from the group consisting of C (O) -heteroaryl, and -N (R ⁶ ) C (O) NR ⁶ R ⁷ ; R ¹² is H, alkyl, aryl, and halo, -CF ₃ , -OH, alkoxy, -OCF ₃ , -CN, -NH ₂ , -C (O) O-alkyl, -OC (O) -alkyl,- C (O) O-aryl, -OC (O) -aryl, -C (O) NR ⁶ R ⁷ , -alkylene-NR ⁶ R ⁷ , -N (R ⁶ ) C (O) -alkyl, -N One or more substituents independently selected from the group consisting of (R ⁶ ) C (O) -aryl, -N (R ⁶ ) C (O) -heteroaryl and -N (R ⁶ ) C (O) NR ⁶ R ⁷ Selected from the group consisting of substituted aryl; m is an integer from 0 to 3, and when m is greater than 1, the m residues may be the same or different from each other; n is an integer from 0 to 3 and when n is greater than 1, the n residues may be the same or different from each other; o is an integer from 0 to 3, and when o is greater than 1, o residues may be the same or different from each other; Provided that m + n + o is 1, 2, 3 or 4; p is an integer from 0 to 4, and if p is greater than 1, the p residues may be the same or different from each other; r is an integer from 0 to 4 and when r is greater than 1, the r residues may be the same or different from each other; s is an integer from 0 to 3, and when s is greater than 1, the s residues may be the same or different from each other; Z is heterocycloalkyl, substituted heterocycloalkyl, -NH ₂ , -NH (alkyl), -N (alkyl) ₂ , wherein each alkyl is the same or different], -NH (cycloalkyl), -NH (Substituted cycloalkyl), -N (alkyl) (cycloalkyl), -N (alkyl) (substituted cycloalkyl), -NH (aralkyl), -NH (substituted aralkyl), -N (alkyl) (Aralkyl), -NH (heterocycloalkyl), -NH (substituted heterocycloalkyl), -N (alkyl) (heterocycloalkyl), -N (alkyl) (substituted heterocycloalkyl), -NH ( Heteroaralkyl), -NH (substituted heteroaralkyl), -NH-alkylene- (cycloalkyl), -NH-alkylene- (substituted cycloalkyl), -N (alkyl) -alkylene- (cyclo Alkyl), -N (alkyl) -alkylene- (substituted cycloalkyl), -NH-alkylene- (heterocycloalkyl), -NH-alkylene- (substituted heterocycloalkyl), -N (alkyl) -Alkylene-(heterocycloalkyl), -N (alkyl) -alkylene- (substituted heterocyclo Ke)), benzo-fused heterocycloalkyl, substituted benzo-fused heterocycloalkyl, H, and -N (hydroxyalkyl) 2, wherein each alkyl is the same or different; ; Wherein the substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl moiety of the Z group is alkyl, -OH, alkoxy, -OC (O) -alkyl, -OC (O) -aryl , -NH ₂ , -NH (alkyl)-, -N (alkyl) ₂ , wherein each alkyl is the same or different, -NHC (O) -alkyl, -N (alkyl) C (O) -alkyl , -NHC (O) aryl-, -N (alkyl) C (O) -aryl, -C (O) -alkyl, -C (O) -aryl, -C (O) NH ₂ , -C (O) NH (alkyl), -C (O) N (alkyl) ₂ , wherein each alkyl is the same or different, -C (O) O-alkyl, -alkylene-C (O) O-alkyl, pipe By one or more substituents independently selected from the group consisting of lidinyl, pyrrolidinyl, aryl, heteroaryl, and -O-CH ₂ CH ₂ -O- wherein two oxygen atoms are bonded to the same carbon atom Provided that the aryl and heteroaryl moieties of the Z group are not substituted by the —O—CH ₂ CH ₂ —O— group. The compound of claim 1, wherein R ² is — (C ₀ -C ₁₂ ) alkylene-C (0) -Y, — (C ₀ -C ₆ ) alkylene- (C ₃ -C ₆ ) cycloalkylene- ( C ₀ -C ₆ ) alkylene-C (0) -Y,-(C ₀ -C ₁₂ ) alkylene-S (O ₂ ) -Y, and-(C ₀ -C ₆ ) alkylene- (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (0 ₂ ) -Y, wherein alkylene or cycloalkylene is optionally substituted with one or more hydroxy groups, provided that And no hydroxy group is bonded to the bonded carbon atom). Y is

It is selected from the group consisting of; (R ³⁾ each R ³ ₂ is H, -OH, - independently from the group consisting of days (C ₇ -C ₁₃₎ aroyl - (C ₁ -C ₆₎ alkyl, - (C ₁ -C ₆₎ acyl and Selected from; or Residue (R ³ ) ₂ defines a carbonyl group together with the ring carbon shown to be bound in formula (I), provided that when m is an integer greater than 1, one or more carbonyl groups are present in the ring represented by formula (I) Exists; Each of R ^3A and R ^3B is independently selected from the group consisting of H and — (C ₁ -C ₆ ) alkyl; R ⁵ is independently selected from the group consisting of halo, —OH, —CF ₃ and —O— (C ₁ -C ₆ ) alkyl; R ¹¹ is-(C ₆ -C ₁₂ ) aryl, substituted-(C ₆ -C ₁₂ ) aryl,-(C ₆ -C ₁₂ ) heteroaryl, and substituted-(C ₆ -C ₁₂ ) heteroaryl Wherein the substituted-(C ₆ -C ₁₂ ) aryl and substituted-(C ₆ -C ₁₂ ) heteroaryl are at least one halo, -CF ₃ , -OH, or -O- ( Substituted by a C ₁ -C ₆ ) alkyl group; m is 0 or 1; n is O or 1; o is O or 1; The compound of claim 1, wherein R ² is — (C ₀ -C ₁₂ ) alkylene-C (O) -Y, — (C ₀ -C ₆ ) alkylene- (C ₃ -C ₆ ) cycloalkylene- ( C ₀ -C ₆ ) alkylene-C (O) -Y,-(C ₀ -C ₁₂ ) alkylene-S (O) -Y,-(C ₀ -C ₆ ) alkylene- (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (O) -Y,-(C ₀ -C ₁₂ ) alkylene-S (O ₂ ) -Y, and-(C ₀ -C ₆ ) Alkylene- (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (O ₂ ) -Y. The compound of claim 1, wherein R ² is — (C ₃ -C ₆ ) cycloalkylene-C (O) -Y. The compound of claim 1, wherein R ² is —cyclopropylene-C (O) —Y. The compound of claim 1, wherein R ² is — (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-C (0) -Y. The compound of claim 1, wherein R ² is cyclopropylene- (C ₀ -C ₆ ) alkylene-C (O) -Y. The compound of claim 1, wherein R ² is cyclopropylene-CH ₂ -C (O) -Y. The compound of claim 1, wherein R ² is cyclopropylene-CH (OH) —C (O) —Y. The compound of claim 1, wherein R ² is —cyclopropylene-S (O ₂ ) —Y. The compound of claim 1, wherein R ² is — (C ₃ -C ₆ ) cycloalkylene- (C ₀ -C ₆ ) alkylene-S (O ₂ ) —Y. The compound of claim 1, wherein R ² is —cyclopropylene-CH ₂ —S (O ₂ ) —Y. The compound of claim 3 wherein Y is

Compound selected from the group consisting of. The compound of claim 1 wherein Y is

Compound selected from the group consisting of. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1 wherein Y is

Phosphorus compounds. The compound of claim 1, wherein R ² is selected from the group consisting of

. The compound of claim 1 selected from the group consisting of compounds having one of the following structural formulas:

. The compound of claim 1 selected from the group consisting of compounds having one of the following structural formulas:

. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate and / or ester thereof, selected from the group consisting of compounds having the formula:

. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate and / or ester thereof, selected from the group consisting of compounds having the formula:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. A compound of the formula: or a pharmaceutically acceptable salt and / or solvate thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. Compounds of the formula: or pharmaceutically acceptable salts, solvates and / or esters thereof:

. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, ester and / or solvate thereof, together with one or more pharmaceutically acceptable excipients, diluents or carriers. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 30, or a pharmaceutically acceptable salt, ester and / or solvate thereof, together with one or more pharmaceutically acceptable excipients, diluents or carriers. A method of inhibiting gamma-secretase in a patient, comprising administering a therapeutically effective amount of at least one compound according to claim 1 to a patient in need of treatment to inhibit gamma-secretase. A method of treating one or more neurodegenerative diseases in a subject, comprising administering a therapeutically effective amount of one or more compounds according to claim 1 to a Chinese character in need of treatment of the one or more neurodegenerative diseases. A method of inhibiting the deposition of beta amyloid protein in a patient, comprising administering a therapeutically effective amount of at least one compound according to claim 1 to a patient in need of treatment that inhibits the deposition of beta amyloid protein. A method of treating Alzheimer's disease in a patient, comprising administering a therapeutically effective amount of at least one compound according to claim 1 to a patient in need of treatment of Alzheimer's disease. The compound of claim 1 in purified form.